NZ738303A - Quinazolinone derivatives for use in treating and/or preventing non-cardiovascular inflammatory diseases - Google Patents

Abstract

Analogues of 2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one for the treatment of cardiovascular disorders, non-cardiovascular inflammatory diseases and/or cancer. Suitable uses include asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s) and others.

Description

QUINAZOLINONE DERIVATIVES FOR USE IN NG AND/OR PREVENTING NON-CARDIOVASCULAR INFLAMMATORY DISEASES This application is a divisional of New Zealand Application No. 719949, filed on 10 May 2016, which is a divisional of New Zealand Application No. 708314, filed on 20 May 2015, which is a divisional of New Zealand Application No. 595747, filed on 16 March 2010, and is related to International Patent Application No. , filed on 16 March 2010 and claiming priority from U.S.

Provisional Patent Application No. 61/161,089, filed on 18 March 2009; each of which is incorporated by reference in its entirety.

The present invention relates to novel compounds that are useful in regulating the expression of interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1), and their use in the treatment and/or prevention of cardiovascular and inflammatory diseases and related disease states, such as, for e, atherosclerosis, asthma, arthritis, cancer, le sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s). The invention also includes pharmaceutical compositions comprising the novel compounds, as well as methods for their preparation.

Coronary heart e (CHD) remains a leading cause of death in rialized nations. A primary cause of CHD is atherosclerosis, a e characterized by the deposition of lipids in the al vessel wall, resulting in a narrowing of the vessel passages and, ultimately leading to hardening of the vascular system.

It is generally accepted that atherosclerosis can begin with local injury to the arterial endothelium, ed by proliferation of al smooth muscle cells from the medial layer to the intimal layer, along with the deposition of lipids and the accumulation of foam cells in the lesion. As the sclerotic plaque develops, it progressively occludes more of the ed blood vessel and can eventually lead to ischemia or infarction. Thus, there is a continued effort to develop treatments to inhibit or prevent the progression of atherosclerosis in patients in need thereof.

Cardiovascular e has been linked to several causative factors, including hypercholesterolemia, hyperlipidemia, and the expression of vascular cell adhesion molecule-1 (VCAM-1) in vascular endothelial cells. VCAM-1 promotes the on of cytes, monocytes, eosinophils, and basophils. Certain melanoma cells can use VCAM-1 to adhere to the endothelium, and VCAM-1 may participate in monocyte recruitment to atherosclerotic sites. As a result, VCAM-1 is of interest as a drug target.

[Text continues on page 2] The VCAM—1 gene is a member of the immunoglobulin (lg) superfamily and encodes a cell-surface sialoglycoprotein expressed by ne- activated endothelial cells. This type—1 membrane protein mediates leukocyte- endothelial cell adhesion and signal transduction, and may play a role in the pment of artherosclerosis and rheumatoid arthritis. VCAM-1, also known as CD106, has several roles in the immune system. The VCAM-1 protein ns six or seven immunoglobulin domains, and is expressed in both large and small s only after endothelial cells are stimulated by cytokines.

Adhesion of leukocytes to the endothelium represents a ental, early event in many inflammatory conditions, including atherosclerosis, autoimmune disorders, and bacterial and viral infections. yte recruitment to the endothelium begins when inducible on molecule receptors on the surface of endothelial cells ct with their counter-receptors on immune cells. Vascular endothelial cells ine which type(s) of yte(s) (e.g., monocytes, lymphocytes, neutrophils) are recruited, by selectively expressing specific adhesion molecules, such as VCAM-1, intracellular adhesion molecule-1 (lCAM-1), and E—selectin.

In the early stage of the atherosclerotic lesion, there is localized endothelial expression of VCAM—1 and selective recruitment of mononuclear leukocytes that express the integrin counter-receptor VLA-4. e of the selective expression of VLA-4 on monocytes and lymphocytes, but not phils, VCAM-1 is important in mediating the selective adhesion of mononuclear leukocytes. Subsequent conversion of leucocytes to foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors, and chemoattractants that help expand leukocyte and platelet recruitment, smooth muscle cell proliferation, endothelial cell activation, and the extracellular matrix synthesis characteristic of maturing atherosclerotic plaques.

VCAM-1 is also a mediator in inflammatory diseases. For example, it is known that the expression of VCAM-1 and lCAM-1 are increased in asthmatics (Pilewski et al. (1995) Am. J. Respir. Cell Mol. Biol. 12, 1-3; Ohkawara et al. (1995) Am J. Respir. Cell Mol. Biol. 12, 4-12). Further examples of non-cardiovascular inflammatory diseases mediated by VCAM-1 include rheumatoid and osteoarthritis, asthma, dermatitis, and multiple sclerosis. Blocking the integrin receptors for VCAM—1 and ICAM-1 (VLA-4 and LFA-1, tively) suppresses both early- and late-phase responses in an ovalbumin—sensitized rat model of allergic airway responses (Rabb etal. (1994) Am. J. Respir. Care Med. 149, 1186—1191). There is also increased expression of endothelial adhesion molecules, including VCAM-1, in the microvasculature of rheumatoid synovium (Koch et al. (1991) Lab. Invest. 64, 313-322; Morales-Ducret et al. (1992) Immunol. 149, 1421—31).

Neutralizing antibodies directed against VCAM-1 or its counter receptor, VLA—4, can delay the onset of diabetes in a mouse model (NOD mice), which spontaneously develop the disease (Yang et al. (1993) Proc. Natl. Acad.

Sci. USA 90, 10494—10498; Burkly et al. (1994) Diabetes 43, 523-534; Baron et al. (1994) J. Clin. . 93, 1700-1708). onal antibodies to VCAM—1 can also have beneficial effects in animal models of allograft rejection, suggesting that tors of VCAM-1 expression may also have utility in preventing transplant rejection (Oroez et al. (1992) Immunol. Lett. 32, 7-12).

VCAM-1 is expressed by cells in both a membrane-bound and soluble form. The soluble form has been shown to induce chemotaxis of vascular endothelial cells in vitro and to stimulate an angiogenic se in rat cornea (Koch et al. (1995) Nature 376, 517—519). Inhibitors of the expression of soluble VCAM—1 have potential therapeutic value in treating es with an enic component, including tumor growth and metastasis (Folkman & Shing (1992) Biol.

Chem. 10931-10934).

Because cardiovascular and inflammatory diseases are currently a leading cause of death and disability in the developed world, there is a strong need to identify new methods and pharmaceutical agents for its treatment. Thus, there is a need to identify and manipulate synthetic compounds that can affect the expression of ors of the matory process, such as, for example, VCAM—1. eukin-6 (IL-6) is a 22—27-kDa secreted glycoprotein that exhibits growth stimulatory and pro—inflammatory activities. lL-6 has also been called interferon-[32 (lFN—BZ), lLinducible 26-kDa protein, hepatocyte—stimulating , cytotoxic T—cell differentiation factor, and B—cell atory factor (Trikha et al. (2003) Clin. Cancer Res. 9, 4653-4665). IL-6 was originally identified in monocytes / macrophages, fibroblasts, and endothelial cells. lL—6 is secreted by various cell types and exerts its activities by binding to a high—affinity receptor complex, consisting of two membrane glycoproteins, an 80—kDa component receptor that binds lL-6 with low affinity (lL— BR) and a signal-transducing ent of 130 kDa (also known as gp130) that does not bind lL-6 itself, but is required for high-affinity binding of lL-6 by the complex. The lL—6R can be cleaved by a transmembrane oproteinase to yield a soluble lL-6R. lL-6 levels are rapidly elevated in the circulation in numerous infectious, inflammatory, autoimmune diseases, and in some cancers, in association with increased synthesis of other cytokines, stimulated by infection, trauma, and immunological challenge. (Trikha et al. (2003) Clin. Cancer Res. 9, 4653-4665). lL-6 has been ated in various diseases and disorders, including multiple a (Rossi et al. (2005) Bone Marrow lantation 36, 771-779), mas (Emilie et al. (1994) Blood 84, 2472-2479), neurological disorders, such as neurodegeneration, astrocytosis, and cerebral enesis (Campbell et al. (1993) Proc. Natl. Acad. Sci. USA 90, 10061~10065), autoimmune ers (e.g., toid arthritis), inflammatory diseases, Alzheimer’s disease, myocardial tion, Paget’s disease, osteoporosis, solid tumors, prostate and bladder cancers (Trikha et al. (2003) Clin. Cancer Res. 9, 665), septic shock, transplants, acute infections of the central nervous system, cardiac myxoma (Wijdenes etal. (1991) Mol. Immunol. 28, 192), tumor—induced cachexia (Cahlin et al. (2000) Cancer Res. 60, 5488—5489), cancer—associated depression, and cerebral edema secondary to brain tumors (Musselman er al. (2001) Am. J. Psychiatry 158, 1252-1257). Inflammation and IL—6 are now specifically thought to be linked to heart attacks (Taubes (2002) Science 296, 242).

Generally, it is known that lL—6 is abnormally produced in some inflammatory, autoimmune, and neoplasmic diseases. It has been proposed that abnormal production of lL—6 is an aspect of the mechanisms of these diseases (Hirano et al. (1990) Immunol. Today, 11, 443-449; Sehgal (1990) Proc. Soc. Exp.

Biol. Med. 195, 183—191; Grau (1990) Eur. Cytokine Net 1, 203—210; Bauer etal. (1991) Ann. Hematol. 62, 203-210; Campbell et al. (1991) J. Clin. Invest. 7, 739— 742; Roodman et al. (1992) J. Clin. Invest. 89, 46-52). In particular, it is known that lL-6 is associated with neuropathological processes, and its level in blood is increased in diseases invading the central nervous system. It has been found that IL-6 increases the level of tau epitope, by stimulating the ia—associated phosphorylation of the tau protein in neuronal cells (Quintanilla et al. (2004) Exp.

Cell Res. 295, 245-257). Mice lacking |L~6 have enhanced resistance to glutamate toxicity and increased viability of neuronal cells (Fisher et al. (2001) J.

Neuroimmunol. 119, 1—9). It has also been found that lL-6 amplifies a calcium influx signal for the neurotransmitter N—methyl-D—aspartate (NMDA), through voltage-sensitive m ls, which provides some evidence that the increased IL-6 level may play a role in inducing pathological changes in central nervous system diseases (Qiu et al. (1998) 18,10445—10456). It has also been reported that the abnormal expression of lL-6 is a enic mechanism in other diseases, including cardiac , uterine cancer (Kishimoto et al. (1988) Ann.

Rev. l. 6, 485), multiple myeloma, histiocytomas (Taga et al. (1987) J.

Exp. Med. 166, 967), plasmacytoma, logical diseases, including plasma cell dyscrasias, leukemia, and lymphoma (Kishimoto (1989) Blood 74, 1; Taga et al. (1987) J. Exp. Med. 166, 967; Klein et al. (1991) Blood 78, 204), proliferative glomerulonephritis, activated multiclonal B-cell (types l-IV) allergic diseases, rheumatoid arthritis (Hirano et al. (1988) Eur. J. Immunol. 18, 1797), es ell eta/(1991) J. Clin. Invest. 87, 739-742), multiple sclerosis, Systemic Lupus Erythematosus, septic shock, bacterial infections, viral infections, osteoporosis (Roodman etal. (1992) J. Clin. Invest. 89, 46-52; Jilka et al. (1992) Science 257, 88-91), chronic immunodeficiency syndrome and autoimmune deficiency syndromes, including AlDS (Med. Immunol. (1988) 15, 195-201 ), and inflammatory diseases, ing inflammatory bowel diseases (such as Crohn’s disease and ulcerative colitis) (WO99/47170). It is known that lL-6 is associated with some central nervous system diseases (Frei et al. (1991) J.

Neuroimmunol. 31 , 147).

Interleukin-6 is secreted by many advanced cancers, such as e—independent prostate , and is believed to be a growth factor for such cancers. Additionally, the secretion of lL—6 by cancer cells is believed to cause cachexia, the wasting syndrome teristic of advanced cancers. Thus, reducing the level of lL-6 would be useful in treating such s. lL-6 also plays a key role in B cell development. Autoimmune diseases with a significant antibody component, such as rheumatoid tis, could be treated by decreasing lL-6 levels. Disorders ing B cell proliferation, such as multiple myeloma and B cell lymphoma, could also be treated by reducing lL—6 activity. Additionally, lL—6 plays an important role in bone remodeling by ing bone resorption.

Reducing lL—6 activity would have the effect of reducing bone resorption and could be used to treat osteoporosis.

Accordingly, there have been various attempts to reduce the levels of lL-6, which are believed to be ated with the pathogenic mechanisms of these various diseases and conditions. A steroid formulation has been used for suppressing the cytokines in the art, but such medicines may causes severe side- effects, such as peptic ulcers, if administered for an extended period.

Anti-lL-6 antibodies have been shown to be effective in treating several diseases and disorders. For example, anti—lL—6 monoclonal antibodies have been shown to block the proliferation of myeloma cells both in vivo and in vitro (Rossi et al. (2005) Bone Marrow Transplantation 36, 771—779).

Administration of anti-lL-6 antibodies to chronic rheumatoid arthritis patients was found to ate the symptoms of the disease (Wendling et al. (1993) J. tol. 20, 259-262). Anti-lL~6 antibodies have also been shown to be effective in treating AIDS—associated lymphoma (Emilie et al. (1994) Blood 84, 2472-2479), and metastatic renal cell carcinoma (Blay et al. (1997) Int. J. Cancer 72, 424-430). Clinical results ing the administration of anti-lL-6 antibodies to treat various other diseases and ers are summarized in Trikha et al. (2003) Clin. Cancer Res. 9, 4653-4665.

Thus, the present invention provides non-naturally ing compounds that are useful for regulating the expression of interleukin—6 (IL-6) and vascular cell adhesion molecule—1 (VCAM-1), as well as the use of such compounds for the treatment and prevention of vascular and inflammatory diseases, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sis, psoriasis, inflammatory bowel diseases, and autoimmune disease(s). t wishing to be bound to theory, it is believed that the compounds of the ion act by inhibiting expression of lL-6 and/or VCAM-1 in the subject receiving the compound. However, less of the mechanism of action, administration of one or more compounds of the present invention will reduce the levels of lL—6 and/or VCAM-1 in the subject and as a result treat or reduce the incidence of cardiovascular and/or inflammatory diseases.

One aspect of the invention provides a method for inhibiting the expression of, or reducing IL-6 and/orVCAM-1 in a subject comprising stering to the subject in need thereof, a therapeutically effective amount of at least one compound of Formula l: Rb3 3-8 sz W R3 Ra3 |Q\ V\ 5 Rag U,N\RCRb6 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q and V are independently selected from CH and en; U is selected from C=O, 0:8, 802, 3:0, SR1, CR1R2, CR1OR2, CR1SR2; R1 and R2 are independently selected from hydrogen and C1-C5 alkyl; Rc is selected from hydrogen, 01-06 alkyl, and C3-C6 cycloalkyl; Ra1, R32, and Ra3 are independently selected from hydrogen, C1-Cs alkyl, C1-C5 alkenyl, C1-Cs alkynyl, C1-06 alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C3-C5 cycloalkyl, wherein Ra1 and R32 and/or R32 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rbg and Rbs are independently selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 alkenyl, C3-C6 lkyl, hydroxyl, and amino; Rb3 and Rb5 are ndently ed from hydrogen, halogen, C1—Cs alkyl, C1-C5 alkoxy, 03-05 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rbe may be connected to form a cycloalkyl or a heterocycle; represents a 3—8 membered ring system wherein: W is selected from carbon and en; Z is selected from CR5R7, NR8, oxygen, sulfur, -S(O)—, and -SOz—; said ring system being optionally fused to another ring selected from cycloakyl, heterocycle, and phenyl, and wherein said ring system is selected from, for example, rings having the structures gt 35 émN‘R’éD 3o ,6?o 31;} 3Q 3V git)R830 3GR123C0R9 R3, R4, and R5 are ndently selected from hydrogen, C1-C5 alkyl, C1- C5 alkenyl, C1—C6 alkynyl, C1-Ce alkoxy, C3-Ce cycloalkyl, aryl, aryloxy, hydroxyl, amino, amide, oxo, —CN, and sulfonamide; R5 and R7 are ndently selected from en, C1—C6 alkyl, C1-C5 alkenyl, C1-C5 alkynyl, C3—Ce cycloalkyl, aryl, halogen, hydroxyl, —CN, amino, sulfonyl, acyl, and amido; R8 is selected from hydrogen, C1—C5 alkyl, C1-Ce alkenyl, C1-C5 alkynyl, acyl, and C3—C5 cycloalkyl; and R9, R10, R11, and R12 are independently ed from hydrogen, C1~Cs alkyl, C1-C6 alkenyl, 01-05 alkynyl, 03-05 cycloalkyl, aryl, heterocycle, hydroxyl, sulfonyl, and acyl, provided that if Q = CH, then at least one of Ra, R82, and R83 is not hydrogen; if Z = NAc, then only one of Ra, R32, or R83 is hydrogen, and Ra1 is not HZOMe; and if Ra1 and Ra3 are both OMe, then R8 is not -C(O)CH20H. in certain embodiments, the method for inhibiting the expression of, or reducing |L-6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula II: Rb3 BT11 Rb2 N\ R83 |Q\ V\ Rb5 / /N Rb6 R32 U \RC or a stereoisomer, tautomer,’ pharmaceutically able salt, or hydrate thereof, Q and V are independently selected from CH and nitrogen; U is selected from C=O, 0:8, 802, 8:0, SR1, CR1R2, CR1OR2, and CR1SR2; R1 and R2 are independently selected from hydrogen and C1-C5 alkyl; Rc is selected from hydrogen, C1-Ce alkyl, and C3-Ce, lkyl; Ra1, R82, and R83 are independently selected from hydrogen, C1-Cs alkyl, 01-05 alkenyl, C1-C5 alkynyl, C1-Cs alkoxy, 03-06 cycloalkyl, halogen, amino, amide, hydroxyl, cycloalkyl, and heterocycle, wherein Ra1 and R32 and/or Rag and Ra3 may be connected to form a cycloalkyl or a heterocycle; sz and Rbs are independently ed from hydrogen, halogen, C1-Cs alkyl, 01-05 alkenyl, 03-05 cycloalkyl, hydroxyl, and amino; Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-Cs alkyl, 01—06 alkoxy, C3-C6 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb5 may be connected to form a cycloalkyl or a cycle; Rm is selected from hydrogen, C1—Ce alkyl, and C3-Ce cycloalkyl; and Rng is selected from 01-05 alkyl, 03-05 cycloalkyl, cycle, aryl, alkenyl, sulfonyl, and acyl, wherein Rm and/or an may be connected with Rb3 and/or Rb5 to form a 5- or 6-membered heterocyclic ring, provided that at least one of Ra, R32, and R33 are not hydrogen; and Rn1 and an are not both methyl or ethyl.

In other ments, the method for inhibiting the expression of, or reducing lL—6 and/or VCAM-1 in a subject, comprises administering a therapeutically ive amount of at least one compound of Formula lll: R83 |Q\ V\ Rb5 / ,N\ Rb6 R32 U Rc (III) or a stereoisomer, tautomer, pharmaceutically able salt, or hydrate thereof, wherein: Q is selected from CR12 and nitrogen; V is selected from CH and nitrogen; U is selected from 0:0, C=S, 802, 8:0, SR1, CR1R2, CR1OR2, CR1SR2; X is selected from oxygen, sulfur, SR1, nitrogen, NR6R7, and CR6R7; Z is selected from unsubstituted C1-Ce alkyl and C1-C5 alkyl substituted with one or more groups selected from 01-03 alkyl, C1-C3 , cyclopropyl, hydroxyl, amino, and halogen; n is selected from 0, 1, 2, 3, 4, or 5; G is ed from heterocycle, cycloalkyl, and aryl; R1 and R2 are independently selected from hydrogen, and C1—C6 alkyl; R6, R7, and R12 are independently ed from hydrogen, 01-06 alkyl, C3- 06 cycloalkyl, heterocycle, C1—Cs alkoxy, and halogen; Rc is selected from hydrogen, 01-05 alkyl, and C3-Ce cycloalkyl; Ra1, R32, and R33 are independently selected from hydrogen, C1-Cs alkyl, C1—C5 alkenyl, C1-Ce alkynyl, 01-05 alkoxy, C3-C6 cycloalkyl, halogen, amino, amide, yl, and heterocycle, wherein Ra1 and R32 and/or R82 and R33 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rbe are independently selected from hydrogen, halogen, C1—Ce alkyl, 03—05 cycloalkyl, C1-Ce> alkenyl, hydroxyl, and amino; and Rb3 and Rb5 are ndently selected from hydrogen, halogen, C1-Cs alkyl, C3—06 cycloalkyl, C1-06 alkoxy, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rbs may be connected to form a cycloalkyl or a heterocycle; provided that if Ra1 and R83 are OMe, and Q = CH, then 3x 2 G" is not H 0 3 \ O\/\ ,N EAN MO 3 wij/Ph O O 7 ,or at least one of Ra, R82, and R83 is not hydrogen; and if R82 or R33 is chloro, then Ra1 is not hydrogen.

In some embodiments, the method for inhibiting the expression of, or reducing |L~6 and/or VCAM—1 in a t, comprises administering a therapeutically effective amount of at least one compound of Formula IV: Q20: ,NH Rb6 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, Q1 is selected from nitrogen and C—Ra1; 02 is ed from nitrogen and C—Raz; Q3 is selected from nitrogen and C—Ras; V is selected from CH and nitrogen; U is selected from C=O, C=S, 802, 8:0, SR1, CR1R2, CR1OR2, CR1SR2; R1 and R2 are independently selected from hydrogen and C1—Cs alkyl; Ra1, R32, and R83 are ndently selected from hydrogen, C1—06 alkyl, C1-Ce alkenyl, C1-C6 alkynyl, C1-Cs alkoxy, Cs-Ce cycloalkyl, amino, amide, and heterocycle, wherein Ra1 and R32 and/or R32 and R83 may be connected to form a cycloalkyl or a cycle; Rb; and Rbe are independently selected from hydrogen, halogen, C1—C5 alkyl, Cg—Ce cycloalkyl, C1—Ce alkenyl, yl, and amino; and Rb3 and Rb5 are independently selected from hydrogen, methyl, ethyl, C3- 06 cycloalkyl, C1-C3 alkoxy, and amino, wherein sz and Rb3 and/or Rb5 and Rbs may be connected to form a cycloalkyl or a heterocycle, provided that if R33 is alkoxy, then Ra1 is not hydrogen; if R82 is be Wor \\/O then Rb3 is not hydrogen; and if sz, Rb5, and Rbs are hydrogen, then Rb3 is not -CH20H.

In a further embodiment, the method for inhibiting the expression of, or reducing lL—6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula V: R83 Q\ N\ Y_A_D ,N Rb or a stereoisomer, tautomer, pharmaceutically able salt, or e thereof, Q is selected from CR5 and nitrogen; U is selected from 0:0, 0:8, 802, 8:0, SR1, CR1R2, CR1OR2, CR1SR2; Y is selected from oxygen, nitrogen, sulfur, NR5, CR5R7; A is C1—C4 alkyl, wherein the alkyl chain may be connected to Y, D, Rb3 and/or Rb5 to form a cycloalkyl or heterocycle; D may be absent or present, and if present is selected from —OR1, —NR1R2; R1 and R2 are independently selected from hydrogen, 01-05 alkyl, 03-06 cycloalkyl, sulfonamide, carboxamide, acyl, and nitrile, wherein R1 and R2 may be connected to form a cycloalkyl or a heterocycle; R5 and R7 are independently selected from hydrogen, C1—Ce alkyl, 03—05 cycloalkyl, 01—05 alkoxy, hydroxyl, and halogen; Ra1, Rag, and R33 are ndently selected from hydrogen, 01—05 alkyl, C1-Ce alkenyl, C1—Cs alkynyl, C1-C5 alkoxy, Cg-Cs lkyl, halogen, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and R32 and/or Rag and R33 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb5 are independently selected from hydrogen, n, 01-06 alkyl, and C3—C6 cycloalkyl; and Rb3 is selected from hydrogen, halogen, 01-06 alkyl, C3—Ce cycloalkyl, C1- Ce , yl, and amino, wherein Rb2 and Rbg and/or Rb5 and Rbs may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra, R82, and R33 is not hydrogen; and if Ra1 and R33 are both hydrogen, and Y = nitrogen, then R32 is not hydrogen, -OAc, or —OMe.

The invention also es pharmaceutical compositions comprising one or more compounds of the invention, (i.e., compounds of Formula I, Formula II, Formula Ill, Formula IV, and Formula V, and stereoisomers, ers, pharmaceutically acceptable salts, and hydrates of compounds of a I, II, III, IV, and V) together with at least one pharmaceutically acceptable carrier, adjuvant, and/or excipient. In on, methods of ing compounds of Formula I, Formula II, Formula Ill, Formula IV, and Formula V, and stereoisomers, tautomers, and pharmaceutically acceptable salts and hydrates thereof are encompassed by the invention.

The invention further provides methods of treatment and/or prevention of cardiovascular and inflammatory es and related disease states by administering to a subject in need thereof, a therapeutically effective amount of one or more compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or tautomers, stereoisomers, pharmaceutically acceptable salts, or hydrates of compounds of Formula I, Formula II, Formula III, Formula IV, and Formula V. The invention also includes methods of regulating the expression of interlukin-6 (IL- 6) and vascular cell adhesion molecule-1 1) in a subject, such as a human, comprising administering a therapeutically effective amount of any of the compounds of the invention bed herein or a pharmaceutically acceptable composition comprising one or more compounds of the invention.

Definitions As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings hout: As used herein, "cardiovascular disease" refers to es, disorders and conditions of the heart and atory system that are mediated by VCAM-1 and/or IL-6. Exemplary cardiovascular diseases, including cholesterol- or lipid-related disorders, include, but are not limited to, acute coronary syndrome, , osclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart e, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholesterolemia, familial combined hyperlipidemia, phalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, dial infarction, y, peripheral vascular disease, reperfusion injury, osis, renal artery atherosclerosis, tic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes us, syndrome X, impotence, multiple sclerosis, Parkinson's diseases and an inflammatory diseases.

As used herein, "inflammatory es" includes diseases, disorders and conditions, that are mediated by VCAM-1 and/or IL-6.

Exemplary inflammatory diseases, include, but are not limited to, tis, asthma, dermatitis, psoriasis, cystic is, post transplantation late and chronic solid organ rejection, le sclerosis, systemic lupus matosus, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ia—reperfusion injury, post—angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina, and small artery disease.

"Subject" refers to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.

As used herein, "treatment" or "treating" refers to an amelioration of a disease or disorder, or at least one nible symptom thereof. In another embodiment, "treatment" or "treating" refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, "treatment" or "treating" refers to inhibiting the progression of a disease or er, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or er. For example, treating a cholesterol disorder may comprise decreasing blood cholesterol levels.

As used herein, "prevention" or "preventing" refers to a reduction of the risk of acquiring a given disease or disorder.

A dash ("—") that is not between two letters or s is used to indicate a point of attachment for a substituent. For example, -CONH2 is ed through the carbon atom.

By "optional" or nally" is meant that the subsequently described event or circumstance may or may not occur, and that the description es instances where the event or circumstance occurs and ces in which is does not. For example, nally substituted aryl" encompasses both "aryl" and ituted aryl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more tuents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or ntly unstable.

As used herein, the term "hydrate" refers to a l form with either a stoichiometric or non-stoichiometric amount of water is incorporated into the crystal structure.

The term "acyl" term as used herein refers to a carbonyl radical attached to an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycyl, aryl, or heteroaryl. Exemplary acyl groups include, but are not limited to, , formyl, propionyl, benzoyl, and the like.

The term "aldehyde" or "formyl" as used herein refers to -CHO.

The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms, referred to herein as (C2- C22)alkenyl, (C2-C8)alkenyl, and (C2-C6)alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propylbutenyl, and 4-(2-methyl butene)-pentenyl.

The term "alkoxy" as used herein refers to an alkyl group attached to an oxygen (-O-alkyl-). "Alkoxy" groups also e an alkenyl group attached to an oxygen ("alkenyloxy") or an alkynyl group attached to an oxygen nyloxy") groups.

Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-22, 1-8, or 1-6 carbon atoms, referred to herein as (C1-C22)alkoxy, (C1-C8)alkoxy, and (C1-C6)alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy and ethoxy.

The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-22, 1-8, or 1-6 carbon atoms, ed to herein as (C1-C22)alkyl, (C1-C8)alkyl, and (C1-C6)alkyl, respectively.

Exemplary alkyl groups include, but are not limited to, , ethyl, propyl, isopropyl, 2-methylpropyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, 2-methyl butyl, 2,2-dimethylpropyl, 2-methylpentyl, ylpentyl, 4-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 2-ethylbutyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, , and octyl.

The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms, referred to herein as (C2- C22)alkynyl, (C2-C8)alkynyl, and (C2-C6)alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, yl, hexynyl, methylpropynyl, 4-methylbutynyl, 4-propylpentynyl, and lhexynyl.

The term "amide" as used herein refers to the form -NRaC(O)(Rb)- or -C(O)NRbRc, wherein Ra, Rb and Rc are each independently selected from alkyl, alkenyl, l, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, cyclyl, and hydrogen. The amide can be attached to another group through the , the nitrogen, Rb, or Rc. The amide also may be cyclic, for example Rb and Rc, may be joined to form a 3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- or 6-membered ring. The term "amide" encompasses groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof. The term "amide" also asses an amide group attached to a y group, e.g., -amide-COOH or salts such as -amide-COONa, an amino group attached to a carboxy group (e.g., -amino-COOH or salts such as -amino-COONa).

The term "amine" or "amino" as used herein refers to the form -NRdRe or -N(Rd)Re-, where Rd and Re are independently selected from alkyl, alkenyl, l, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.

The amino can be attached to the parent molecular group through the nitrogen. The amino also may be , for example any two of Rd and Re may be joined together or with the N to form a 3- to 12-membered ring (e.g., lino or piperidinyl). The term amino also includes the corresponding quaternary ammonium salt of any amino group.

Exemplary amino groups include alkylamino groups, wherein at least one of Rd or Re is an alkyl group.

The term "aryl" as used herein refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system. The aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls. The aryl groups of this invention can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, aryl, heterocyclyl, hydroxyl, , nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, yl, and naphthyl, as well as fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Cs)ary|." The term "arylalkyl" as used herein refers to an alkyl group having at least one aryl substituent (e.g., -aryl-alky|—). Exemplary ky! groups include, but are not limited to, arylalkyls having a clic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Ce)arylalkyl." The term "aryloxy" as used herein refers to an aryl group attached to an oxygen atom. Exemplary aryloxy groups include, but are not limited to, aryloxys having a clic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Cs)aryloxy." The term "arylthio" as used herein refers to an aryl group attached to an sulfur atom. Exemplary arylthio groups include, but are not limited to, arylthios having a clic aromatic ring , wherein the ring comprises 6 carbon atoms, referred to herein as "(Cs)arylthio." The term "arylsulfonyl" as used herein refers to an aryl group attached to a yl group, e.g., —S(O)2-aryl-. Exemplary arylsulfonyl groups include, but are not limited to, arylsulfonyls having a monocyclic aromatic ring system, wherein the ring ses 6 carbon atoms, referred to herein as "(C5)arylsulfonyl." The term "benzyl" as used herein refers to the group henyl.

The term "bicyclic aryl" as used herein refers to an aryl group fused to another aromatic or non~aromatic carbocylic or heterocyclic ring. Exemplary bicyclic aryl groups include, but are not limited to, naphthyl or partly reduced forms thereof, such as di-, tetra—, or hexahydronaphthyl.

The term "bicyclic aryl" as used herein refers to a heteroaryl group fused to another aromatic or non-aromatic carbocylic or cyclic ring.

Exemplary bicyclic heteroaryls include, but are not limited to 5,6— or 6,6—fused systems, wherein one or both rings contain heteroatoms. The term "bicyclic heteroaryl" also encompasses reduced or partly reduced forms of fused aromatic system wherein one or both rings n ring heteroatoms. The ring system may contain up to three heteroatoms, ndently selected from oxygen, nitrogen, and sulfur. The bicyclic system may be optionally substituted with one or more groups selected from alkoxy, aryloxy, alkyl, alkenyl, l, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, yl, ic acid, sulfonamide, and thioketone. Exemplary ic heteroaryl’s include, but are not limited to, quinazolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl, and uranyl.

The term "carbamate" as used herein refers to the form ~RgOC(O)N(Rh)-, —RgOC(O)N(Rh)Ri-, or —OC(O)NRhRi, wherein R9, Rh and R] are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates (e.g., wherein at least one of R9, Rh and R; are independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).

The term "carbonyl" as used herein refers to ~C(O)—.

The term "carboxy" as used herein refers to —COOH or its ponding carboxylate salts (e.g., -COONa). The term carboxy also includes "carboxycarbonyl," e.g. a carboxy group attached to a carbonyl group, e.g., ~C(O)- COOH or salts, such as —C(O)—COONa.

The term "cyano" as used herein refers to -CN.

The term "cycloalkoxy" as used herein refers to a cycloalkyl group attached to an oxygen.

The term "cycloalkyl" as used herein refers to a saturated or unsaturated cyclic, bicyclic, or d bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, ed to herein as 8)cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes , cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, kyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other lkyl saturated or unsaturated, aryl, or heterocyclyl groups.

The term "dicarboxylic acid" as used herein refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof. Exemplary oxylic acids include alkyl dicarboxylic acids. Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, l, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, yl, sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include, but are not limited to succinic acid, ic acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, c acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid, and terephthalic acid. Dicarboxylic acids further include ylic acid derivatives thereof, such as anhydrides, imides, hydrazides (for example, succinic ide and succinimide).

The term "ester" refers to the structure -C(O)O-, -C(O)O-Rj-, -RkC(O)ORj- , or -RkC(O)O-, where O is not bound to hydrogen, and Rj and Rk can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl. Rk can be a hydrogen, but Rj cannot be hydrogen. The ester may be cyclic, for e the carbon atom and Rj, the oxygen atom and Rk, or Rj and Rk may be joined to form a 3- to 12- membered ring. Exemplary esters include, but are not limited to, alkyl esters wherein at least one of Rj or Rk is alkyl, such as -O- C(O)—alkyl, -C(O)—O-a|kyl—, and -a|ky|—C(O)—O-alkyl-. Exemplary esters also include aryl or heteoraryl esters, e.g. wherein at least one of Rj or Rk is a heteroaryl group such as pyridine, pyridazine, pyrmidine and pyrazine, such as a nicotinate ester.

Exemplary esters also include reverse esters having the structure —RkC(O)O-, where the oxygen is bound to the parent molecule. Exemplary reverse esters include succinate, ninate, L-argininate, L-lysinate and D-lysinate. Esters also include carboxylic acid anhydrides and acid halides.

The term "ether" refers to the structure -R|O-Rm_, where R] and Rm can independently be alkyl, alkenyl, l, aryl, cycloalkyl, heterocyclyl, and ether. The ether can be attached to the parent molecular group through R] or Rm.

Exemplary ethers include, but are not limited to, alkoxyalkyl and alkoxyaryl groups. Ethers also includes polyethers, e.g., where one or both of R1 and Rm are ethers.

The terms "halo" or "halogen" or "Hal" as used herein refer to F, Cl, Br, or |.

The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms. "Haloalkyls" also encompass alkenyl or alkynyl groups substituted with one or more n atoms.

The term "heteroaryl" as used herein refers to a mono-, bi—, or multi- , aromatic ring system containing one or more heteroatoms, for example 1—3 heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, y, alkyl, l, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.

Heteroaryls can also be fused to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, dyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)— and (1,2,4)—triazoly|, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and yl. Exemplary heteroaryl groups e, but are not limited to, a clic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 atoms, referred to herein as "(Cg-C5)heteroaryl." The terms "heterocycle," "heterocyclyl," or ocyclic" as used herein refer to a ted or unsaturated 3-, 4-, 5-, 6-, or 7—membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heterocycles can be aromatic oaryls) or non-aromatic.

Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, y, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, yl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heterocycles also include bicyclic, lic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryl, lkyl, and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, ofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, azolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms "hydroxy" and "hydroxyl" as used herein refers to -OH.

The term "hydroxyalkyl" as used herein refers to a hydroxy attached to an alkyl group.

The term "hydroxyaryl" as used herein refers to a hydroxy ed to an aryl group.

The term e" as used herein refers to the structure —C(O)-Rn (such as acetyl, H3 or ~Rn-C(O)-RO-. The ketone can be attached to another group through Rn or R0. Rn or R0 can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl, or Rn and R0 can be joined to form a 3- to 12-membered ring.

The term ster" as used herein refers to an analogue of a dicarboxylic acid wherein one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or salt of a carboxylic acid. es of monoesters include, but are not limited to, to monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic, and maleic acid.

The term "nitro" as used herein refers to -NO2.

The term "perfluoroalkoxy" as used herein refers to an alkoxy group in which all of the hydrogen atoms have been replaced by fluorine atoms.

The term "perfluoroalkyl" as used herein refers to an alkyl group in which all of the en atoms have been replaced by ne atoms. Exemplary perfluroalkyl groups include, but are not limited to, C1-C5 perfluoroalkyl, such as oromethyl.

The term "perfluorocycloalkyl" as used herein refers to a cycloalkyl group in which all of the hydrogen atoms have been replaced by fluorine atoms.

The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. The phenyl group can also be fused to a cyclohexane or cyclopentane ring. Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.

The term "phosphate" as used herein refers to the ure -OP(O)O2-, -RxOP(O)O2-, O2Ry-, or -RxOP(O)O2Ry-, wherein Rx and Ry can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cyclyl, and en.

The term "sulfide" as used herein refers to the structure -RzS-, where Rz can be alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl. The sulfide may be cyclic, forming a 3 to 12-membered ring. The term "alkylsulfide" as used herein refers to an alkyl group attached to a sulfur atom.

The term "sulfinyl" as used herein refers to the structure -, -RpS(O)O-, -RpS(O)ORq-, or -S(O)ORq-, wherein Rp and Rq can be alkyl, alkenyl, aryl, arylalkyl, lkyl, haloalkyl, heteroaryl, cyclyl, and hydroxyl. Exemplary sulfinyl groups include, but are not limited to, alkylsulfinyls n at least one of Rp or Rq is alkyl, alkenyl, or alkynyl.

The term "sulfonamide" as used herein refers to the structure -(Rr)-NS (O)2-Rs- or -Rt(Rr)-N-S(O)2-Rs, where Rt, Rr, and Rs can be, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides include alkylsulfonamides (e.g., where Rs is alkyl), arylsulfonamides (e.g., where Rs is aryl), cycloalkyl sulfonamides (e.g., where Rs is cycloalkyl), and heterocyclyl sulfonamides (e.g., where Rs is cyclyl).

The term "sulfonate" as used herein refers to -OSO3-. Sulfonate includes salts such as -OSO3Na, -OSO3K and the acid -OSO3H.

The term "sulfonic acid" refers to -SO3H- and its corresponding salts (e.g., -SO3K- and -SO3Na-).

The term "sulfonyl" as used herein refers to the structure RuSO2-, where Ru can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and cyclyl (e.g., alkylsulfonyl).

The term "alkylsulfonyl" as used herein refers to an alkyl group attached to a sulfonyl group. "Alkylsulfonyl" groups can optionally n alkenyl or alkynyl groups.

The term "thioketone" refers to the structure -Rv-C(S)-Rw-. The ketone can be attached to another group h Rv or Rw. Rv or Rw can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl, or Rv and Rw can be joined to form a 3- to 12- ed ring.

"Alkyl" groups can be substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, l, l, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, ketone, heteroaryl, heterocyclyl, hydroxyl, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, amide, thioketone, ureido, and N. The substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.

"Alkenyl," "alkynyl", "alkoxy", "amino" and "amide" groups can be substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, , halogen, haloalkyl, heteroaryl, heterocyclyl, yl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N. The substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.

As used herein, a "suitable substituent" refers to a group that does not y the synthetic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: C1-22, C1-8, and C1-6 alkyl, l or alkynyl; C1-6 aryl, C2-5 heteroaryl; C3-7 cycloalkyl; C1-22, C1-8, and C1-6 alkoxy; C6 aryloxy; -CN; -OH; oxo; halo, y; amino, such as -NH(C1-22, C1-8, or C1-6 alkyl), -N(C1-22, C1-8, and C1-6 alkyl)2, -NH((C6)aryl), or -N((C6)aryl)2; formyl; ketones, such as -CO(C1-22, C1-8, and C1-6 alkyl), -CO((C6 aryl) esters, such as -CO2(C1-22, C1-8, and C1-6 alkyl) and -CO2 (C6 aryl). One of skill in art can readily choose a suitable tuent based on the stability and pharmacological and synthetic activity of the compound of the invention.

As used herein, "inhibiting" refers to blocking, suppressing, or in any other way, reducing the expression of IL-6 mRNA and/or VCAM-1 mRNA, and/or the level of protein.

As used herein, "reducing" refers to ng the overall levels of IL-6 and/or VCAM-1, e.g., by inhibiting the expression of, eliminating, and/or ing IL-6 mRNA and/or VCAM-1 mRNA, and/or the level of protein.

The term "pharmaceutically acceptable carrier" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption ng agents, and the like, that are ible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.

The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

The term "pharmaceutically acceptable composition" as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable prodrugs" as used herein represents those gs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, surate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the nds of the invention. A discussion is provided in Higuchi et al., "Prodrugs as Novel Delivery s," ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible rs in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The term "pharmaceutically acceptable )" refers to salts of acidic or basic groups that may be present in compounds used in the present itions. Compounds included in the present compositions that are basic in nature are e of forming a wide variety of salts with s inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non— toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, blsulfate, phosphate, acid ate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, e, gentisinate, fumarate, ate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis—(2-hydroxy-3—naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present itions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable s. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, , lithium, zinc, ium, and iron salts.

The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers" when used herein consist of all geometric isomers, enantiomers or diastereomers.

These nds may be designated by the symbols "R" or S" depending on the configuration of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and reomers. Mixtures of enantiomers or diastereomers may be designated "(i)" in nomenclature, but the skilled artisan will recognize that a structure may contain an implicit chiral center.

Individual stereoisomers of nds of the present invention can be prepared tically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.

These methods of resolution include, but are not d to (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active ing agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. isomeric mixtures can also be ed into their component stereoisomers by well known methods, including, but not limited to chiral—phase gas chromatography, chiral-phase high performance liquid tography, crystallizing the compound as a chiral salt complex, and/or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.

Geometric isomers can also exist in the nds of the t invention. The present invention encompasses the various geometric s and mixtures thereof resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a carbocyclic ring.

Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration wherein the terms "Z" and "E’ are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the E and Z s.

[O97] Substituents around a carbon-carbon double bond alternatively can be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond. The arrangements of substituents around a carbocyclic ring are designated as "cis" or "trans." The term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on te sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans." The compounds sed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. For example, any claim to nd A below is understood to e tautomeric structure B, and vice versa, as well as mixtures thereof.

Rb3 Rb3 Rb2 sz Ra3 Q\ V\ R33 | Rb5 Q\ V\ 1 Rb5 / NH Rb6 / /N Rio6 Ra2 Ra2 R31 0 R81 OH A B Exemplam Embodiments Formula | Methods and Compounds In certain embodiments, the method for inhibiting the expression of, or reducing lL-6 and/or VCAM-1 in a t, comprises administering a eutically effective amount of at least one compound of Formula I: sz R3 R33 IQ\ V\ R5 / ,N Rb6 Ra2 U \RC or a stereoisomer, tautomer, pharmaceutically able salt, or hydrate thereof, wherein: EQRB is?!"Nigel;R5 R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, C1-C6 alkenyl, C1—C¢~> alkynyl, C1-C6 alkoxy, C3-Ce lkyl, aryloxy, aryl, yl, amino, amide, oxo, -CN, and sulfonamide; and R8 is ed from en, C1—C5 alkyl, C1-C6 alkenyl, acyl, and C1-C6 alkynyl.

In some embodiments, the method for inhibiting the expression of, or reducing lL-6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula I, wherein: R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1—C5 alkynyl, C1-C5 alkoxy, C3-C5 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R9 and R10 are independently selected from hydrogen, C1-C6 alkyl, C1—C5 alkenyl, C1-C6 alkynyl, 03-06 cycloalkyl, aryl, heterocycle, sulfonyl, carbamate, carboxamide, and acyl.

In some embodiments, the method for inhibiting the sion of, or reducing lL-6 and/or VCAM—1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula I, wherein: ‘ ,R8 3-8 1J4 771": R3 \ R4 R4 R5 .

R3 and R4 are independently selected from hydrogen, C1-Ce alkyl, C1—Cg alkenyl, C1—Ce alkynyl, C1-Ce , 03-06 cycloalkyl, y, aryl, hydroxyl, amino, amido, oxo, —CN, and sulfonamide; and R8 is selected from hydrogen, C1-Ce alkyl, C1—C6 alkenyl, C1—C6 l, acyl, and C3-C5 cycloalkyl.

In some embodiments, the method for inhibiting the sion of, or reducing lL—6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula I, wherein: U is C=O; Rc is hydrogen; R82 is hydrogen; Ra1 and R33 are independently selected from 01-06 alkoxy, hydrogen, and halogen; sz, Rb3, Rbs, and Rbs are each hydrogen; 3-8 NR8 M NR12 W R3 N\/\ R4 4 R5 is selected from 3NR\3\NR8OR, and R3 and R4 are independently selected from hydrogen and C1-C6 alkyl; R8 is selected from C1-C5 alkyl and hydrogen; and R9, R10, R11, and R12 are independently selected from C1-C6 alkyl, hydrogen, acyl, and sulfonyl. in some embodiments, the method for inhibiting the expression of, or reducing -6 and/or VCAM—1 in a subject, comprises stering a therapeutically ive amount of at least one compound of Formula I, wherein: U is C=O; Rc is hydrogen; Rag is hydrogen; R31 and R33 are independently selected from methoxy, hydrogen, and halogen; sz, Rbs, Rb5, and Rbs are each hydrogen; NR10 811 3—8 R€\NR R12 R4 4 R5 is selected from R%N\>RR38 3N , , R€\NR8 and 3N R3 and R4 are ndently selected from hydrogen and methyl; R3 is selected from hydrogen, hydroxyethyl, butyl, acetyl, isopropyl, 4- hexanoyl, 4—isobutyryl, benzoyl, 4-fluorobenzoyl, 4—picolinoyl, 4-nicotinoyl, 4- isonicotinoyl, thiophene—2—carbonyl, romethyl-1H-pyrazolecarbonyl, trifluoropropanoyl, 2,5-dichlorothiopene—3—carbonyl, cyclopropanecarbonyl, 4-fluorobenzyl, benzyl, 2,2,2-trifluoroethyl, tertbutoxycarbonyl, and formyl; R9 and R10 are independently selected from hydrogen, , cyclopropylmethyl, and acetyi; and R11 and R12 are independently selected from hydrogen, acetyl, methanesulfonyl, dimethylaminocarbonyl, benzoyl, benzyl, ethyl, and isopropyl.

In n embodiments, the method for inhibiting the expression of, or reducing lL-6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one nd of a I selected from: ,7-dimethoxy-Z—(4—morpholinophenyl)quinazolin~4(3H)—one; 2—(4—((3R,58)acetyl-3,5-dimethylplperazin-1—yl)phenyl)-5,7- dimethoxypyrldo[2,3—d]pyrimidin—4(3H)—one; 2—(4—(4-hydroxypiperidin~1-y|)phenyl)—5,7—dimethoxypyrido[2,3-d]pyrimidin- 4(3H)-one; 2-(4—((3R,58)—4—acetyl-3,5-dimethylpiperazin-1—y|)phenyl)methoxy(2— methoxyethoxy)quinazolin-4(3H)—one; 2—(4-(4—lsopropylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin~4(3H)—one; 2-(4-(4—acetylpiperazin-1—y|)phenyl)-5,7—dimethoxyquinazolin—4(3H)—one; ,7-dimethoxy-2—(4-(piperazinyl)phenyl)quinazolin~4(3H)—one; N-(1—(4—(5,7-dimethoxy—4—oxo-3,4-dihydroqulnazolin—2—yl)phenyl)piperidin yl)acetamide; N-(1~(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolin—2—yl)phenyl)piperidin-4— yl)methanesulfonamide; 3-(1-(4—(5,7-dimethoxy-4—oxo—3,4-dihydroquinazolin-2—yl)phenyl)plperidin yl)—1,1-dimethylurea; 2—(4-(4-hexanoylpiperazin—1—yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)—one; 2—(4-(4—isobutyrylpiperazin—1-yl)phenyl)—5,7-dimethoxyquinazolin—4(3H)—one; 2-(4-(4—benzoylpiperazin—1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)—one; 2-(4-(4—(4—fluorobenzoyl)piperazinyl)phenyl)—5,7-dimethoxyquinazolin- 4(3H)—one; 4—(5,7-dimethoxyoxo-3,4—dihydroquinazollnyl)phenyl)piperidln yl)benzamide; ,7-dimethoxy-Z-(4-(4-picolinoylpiperazin—1-yl)phenyl)quinazolin-4(3H)—one; ,7-dimethoxy-Z—(4~(4-nicotinoylpiperazin—1-yl)phenyl)quinazolin—4(3H)-one; 2-(4—(4-isonicotinoylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin—4(3H)- ,7—dimethoxy(4—(4—(thiophene—2-carbonyl)piperazin~1 - yl)phenyl)quinazolin-4(3H)—one; 2-(4—(4-(5-chloromethyl—1H—pyrazoIecarbonyl)piperazin-1—y|)phenyl)— ,7-dimethoxyquinazolin-4(3H)—one; ,7-dimethoxy—2—(4—(4-(3,3,3-trifluoropropanoyl)piperazin-1 - nyl)quinazolin-4(3H)—one; 2—(4-(4-(2,5—dichlorothiophene—3-carbonyl)piperazinyl)phenyI)-5,7— dimethoxyquinazolin-4(3H)—one; 2-(4-(4-(cyclopropanecarbonyl)piperazin~1-y|)phenyI)-5,7- dimethoxyquinazolin-4(3H)—one; 2—(4-(4-(4—fluorobenzyl)piperaziny|)phenyl)-5,7~dimethoxyquinazo|in- 4(3H)—one; 2-(4—(4-benzylpiperazin-1—y|)pheny|)—5,7—dimethoxyquinazolin—4(3H)-one; 4—(2,2,2-trifluoroethyl)piperaziny|)pheny|)quinazolin-4(3H)—one; 2-(4-(4-butylpiperaziny|)pheny|)-5,7-dimethoxyquinazolin—4(3H)—one; 2-(4-(4-acetyI-1,4—diazepan-1—yl)phenyI)-5,7—dimethoxyquinazolin—4(3H)— 2-(4—(1,4—diazepanyl)phenyI)-5,7—dimethoxyquinazolin-4(3H)-one; ,7—dimethoxy-2—(4-(4—methyl-1,4-diazepan—1-y|)pheny|)quinazolin—4(3H)- N-(1-(4-(5,7-dimethoxy—4—oxo-3,4-dihydroquinazolin—Z-yl)phenyl)piperidin—4— y|)—N—ethy|acetamide; 2-(4-((3R,58)—4-acetyI-3,5-dimethylpiperazin~1—y|)phenyI)—5,7- dimethoxyquinazolin-4(3H)—one; 2-(4-((3R,5S)-3,5-dimethylpiperaziny|)phenyl)—5,7-dimethoxyquinazolin— 4(3H)-one; 2-(4-(4—acetyImethylpiperazin—1-yl)phenyI)—5,7-dimethoxyquinazolin- 4(3H)—one; 4-(5,7-dimethoxy—4-oxo—3,4-dihydroquinazolin—2-yl)phenyl)pyrrolidin- 3—yl)acetamide; 2-(4—(4-isopropylpiperazin—1-yl)phenyl)—8—methoxyquinazolin-4(3H)—one; 2-(4-(4~(2—hydroxyethyl)piperaziny|)phenyl)—5,7-dimethoxyquinazolin- 4(3H)-one; 4-(5,7-dimethoxy—4—oxo-3,4—dihydroquinazolin-Z—yl)phenyl)piperidin y!)—N—isopropylacetamide; —chIoro-2—(4-(4-isopropylpiperazin-1—y|)phenyl)quinazolin-4(3H)—one; 2-(4—((3R,58)isopropyl—3,5-dimethylpiperazin—1—yl)phenyI)—5,7— dimethoxyquinazolin—4(3H)-one; ,7-dimethoxy—Z-(4-(piperidin—4-yl)phenyl)quinazolin—4(3H)-one; ,7-dimethoxy-Z-(4-(3—(methylamino)pyrro|idinyl)phenyl)quinazolin- 4(3H)-one; tert—butyl 4—(4-(5,7—dimethoxy—4—oxo—3,4-dihydroquinazolin yl)phenyl)piperidine—1-carboxylate; N-(1—(4-(5,7—dimethoxy-4—oxo-3,4-dihydroquinazolin-Z-yl)phenyl)pyrrolidin— 3-yl)~N—methylacetamide; 2—(4—(4-(isopropylamino)piperidinyl)phenyI)-5,7-dimethoxyquinazolin- 4(3H)—one; 1—acetylpiperidin-4—yl)phenyl)-5,7—dimethoxyquinazolin-4(3H)—one; ,7-dimethoxy-Z-(4-(3-methylpiperazin—1-y|)pheny|)quinazolin-4(3H)-one; N-benzyI-N—(1—(5-(5,7-dimethoxyoxo-3,4-dihydroquinazolin-Z—yl)pyridin- 2-y|)piperidin-4~y|)acetamide; 2-(6-(4-(benzylamino)piperidinyl)pyridinyl)—5,7—dimethoxyquinazolin- 4(3H)—one; 4-(4-(5,7~dimethoxyoxo—3,4-dihyd roquinazoliny|)phenyl)piperazine-1 — carbaldehyde; 2-(4—(2—(1—acetylazetidinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(3-(cyclopropylmethylamino)pyrrolidinyl)phenyl)-5,7— oxyquinazolin-4(3H)—one; and ,7-dimethoxy-Z-(4-(4—oxopiperidinyl)phenyl)pyrido[2,3-d]pyrimidin- 4(3H)—one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

Another aspect of the invention provides compounds of Formula I: Rbs 3-8 sz R3 R83 IQ\ V\ 5 R32 U,N\R0Rb6 and stereoisomers, tautomers, pharmaceutically acceptable salts, and es thereof, wherein: Q and V are independently selected from CH and nitrogen; U is selected from 0:0 and 802; W is selected from carbon and en; Rc is selected from en, C1-Ca alkyl, and 03—05 cycloalkyl; Ra1, R32, and Ra3 are independently selected from hydrogen, C1-Cs alkyl, 01-06 alkenyl, C1-Cs alkynyl, C1—C5 alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and 03-05 cycloalkyl, wherein Ra1 and R82 and/or R32 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rbg and Rba are independently selected from hydrogen, halogen, 01-06 alkyl, C1-Ca alkenyl, C3-C5 cycloalkyl, hydroxyl, and amino; Rb3 and Rb5 are independently selected from en, halogen, 01—05 alkyl, C1-Ce alkoxy, 03-05 cycloalkyl, hydroxyl, and amino, n sz and Rb3 and/or Rb5 and Rbs may be connected to form a cycloalkyl or a heterocycle; represents a 3~8 membered ring system wherein: W is selected from carbon and nitrogen; Z is selected from CR6R7, NR8, oxygen, sulfur, -S(O)—, and -SOz-; said ring system being optionally fused to another ring selected from cycloakyl, heterocycle, and phenyl, and wherein said ring system is selected from, for example, rings having the structures at 3"" 3" 39 3’5 363 9 O??? 2'? éNj grid R830 36R12 éOSBJR 5533r0 1° r03 to 30 30 30 30;O 99 R3, R4, and R5 are independently selected from en, C1-Cs alkyl, C1— C5 alkenyl, 01-06 l, C1-Cs alkoxy, C3-Ce cycloalkyl, aryl, aryloxy, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; R6, and R7 are independently selected from hydrogen, 01-06 alkyl, C1—Ce l, C1—C5 alkynyl, C3-C5 cycloalkyl, aryl, halogen, hydroxyl, acyl, and -CN; R8 is selected from hydrogen, C1-C9> alkyl, 01-06 alkenyl, C1-Ce alkynyl, C3- 06 cycloalkyl and acyl; and R9, R10, R11, and R12 are independently selected from en, C1-C5 alkyl, C1—C6 alkenyl, C1—CG alkynyl, C3-Ce cycloalkyl, aryl, hydroxyl, sulfonyl, and acyl, ed that if Q = CH, then at least one of Ra, R82, and R33 is not hydrogen; if Z = NAc, then only one of Ra, R32, and Rag is hydrogen, and Ra1 is not —OCHzCH20Me; if Ra1 and Ra3 are both OMe, than R8 is not -C(O)CH20H; and further provided that the compound of Formula I is not 5,7-dimethoxy(4- morpholinophenyl)quinazolin-4(3H)—one, 5,7-dimethoxy—2-(4-(4-methylpiperazin yl)phenyl)quinazolin-4(3H)—one, or 2—(4—(1-cyclopentylpiperidin-4—yl)phenyl)—3- methquuinazolin—4(3H)-one.

Some embodiments provide compounds of Formula I, and stereoisomers, tautomers, ceutically acceptable salts, and hydrates thereof, wherein: Evflfs3341:;R5 R3 and R4 are independently selected from hydrogen, C1-Ce alkyl, C1-Ce alkenyl, 01—05 alkynyl, C1-Ce alkoxy, C3-Ce cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R8 is ed from hydrogen, 01-06 alkyl, C1-Ce alkenyl, C1-Cs alkynyl, acyl, and C3-C5 cycloalkyl.

Other embodiments provide compounds of Formula I, and stereoisomers, ers, pharmaceutically acceptable salts, and hydrates thereof, wherein: R3 ' 3—8 f R10 E R3 3N \/\ R4 R4 R .

IS R3 and R4 are independently selected from hydrogen, C1—C6 alkyl, (31-05 alkenyl, 01-05 alkynyl, C1~C5 alkoxy, Cg-Ce lkyl, y, aryl, yl, amino, amide, oxo, -CN, and sulfonamide; and R9 and R10 are independently selected from hydrogen, C1-Ce alkyl, C1—C6 alkenyl, C1-C6 alkynyl, 03-05 cycloalkyl, aryl, heterocycle, sulfonyl, carbamate, carboxamide, and acyl.

Still other embodiments provide compounds of Formula I, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: R3 and R4 are independently selected from hydrogen, C1-Ce alkyl, C1—Cs alkenyl, 01-05 alkynyl, 01—05 alkoxy, 03-05 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, —CN, and amide; and R9 and R10 are independently selected from hydrogen, C1-Cs alkyl, C1-Ce alkenyl, C1-Cs l, 03—05 cycloalkyl, aryl, cycle, sulfonyl, amide, carbamate, and acyl.

Certain embodiments provide compounds of Formula I, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: 3-8 $N’R8 w R3 \JR R4 4 R5 .

R3 and R4 are independently selected from hydrogen, C1-Cs alkyl, C1-Cs alkenyl, C1-C6 l, C1-Ce alkoxy, C3-C5 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R8 is selected from en, C1—C5 alkyl, C1-C6 alkenyl, C1-C5 l, acyl, and 03-05 cycloalkyl.

Some embodiments provide compounds of Formula I, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, U is 0:0 Rc is hydrogen; R82 is hydrogen; Ra1 and R33 are independently selected from 01-05 , hydrogen, and halogen; sz, Rb3, Rb5, and Rbe are each hydrogen; 3-8 NR8 M [{LR12 HEW R3 R4 R4§N\/\R4 R5 is selected from 3N 3NPWR8\/\R4 and R3 and R4 are independently selected from hydrogen and C1-05 alkyl; R8 is selected from C1-Cs alkyl, and en; and R9, R10, R11, and R12 are independently selected from 01—05 alkyl, hydrogen, and sulfonyl.

Other embodiments provide compounds of Formula I, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, U is C=O Rc is hydrogen; Rag is hydrogen; Ra1 and R83 are independently selected from methoxy, hydrogen, and halogen; sz, Rb3, Rb5, and Rbe are each hydrogen; R R3 B11 8\N’R8 \ N 3—8 l R12 1'2; R \l 3N \ 3 \/ R4 R4 3N0/ R4 R5 is selected from , , , %N\/\JR4 and ; R3 and R4 are independently selected from en and methyl; R8 is selected from hydrogen, yethyl, butyl, acetyl, isopropyl, 4- hexanoyl, 4-isobutyryl, benzoyl, 4-fluorobenzoyl, 4—picolinoyl, 4-nicotinoyl, 4— isonicotinoyl, thiophene—Z-carbonyl, 5—chloro—1-methyl-1H—pyrazoIecarbonyl, 3,3,3—trifluoropropanoyl, 2,5—dichlorothiopene-B-carbonyl, cyclopropanecarbonyl, 4-fluorobenzyl, benzyl, 2,2,2-trifluoroethyl, tertbutoxycarbonyl, and formyl; R9 and R10 are independently selected from hydrogen, methyl, cyclopropylmethyl, and acetyl; and R11 and R12 are independently selected from hydrogen, acetyl, methanesulfonyl, dimethylaminocarbonyl, benzoyl, benzyl, ethyl, and isopropyl. in one ment, compounds of Formula l are selected from: 2-(4—((3R,5S)—4-acetyl—3,5-dimethylpiperazin—1~yl)phenyl)-5,7— dimethoxypyrido[2,3-d]pyrimidin-4(3H)—one; 2-(4-(4—hydroxypiperidinyl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin— 4(3H)—one; (3R,5S)—4~acetyl-3,5-dimethylpiperaziny|)phenyl)—5—methoxy(2- yethoxy)quinazolin-4(3H)-one; 2-(4-(4-isopropylpiperazinyl)phenyl)~5,7-dimethoxyquinazolin-4(3H)—one; 2-(4-(4-acetylpiperazinyl)phenyl)—5,7—dimethoxyquinazolin-4(3H)—one; ,7-dimethoxy—2—(4-(piperazin—1—yl)phenyl)quinazolin-4(3H)-one; N~(1-(4-(5,7-dimethoxyoxo—3,4-dihydroquinazolin-2—yl)phenyl)piperidin tamide; N-(1—(4-(5,7—dimethoxy—4—oxo-3,4—dihydroquinazolinyl)phenyl)piperidin-4— y|)methanesulfonamide 3-(1-(4-(5,7-dimethoxyoxo—3,4-dihydroquinazolin—Z-y!)phenyl)piperidin—4— yl)-1,1-dimethylurea; 2—(4—(4-hexanoyipiperaziny|)pheny|)-5,7-dimethoxyquinazolin—4(3H)-one; 2-(4-(4-isobutyrylpiperazin—1-y|)phenyI)—5,7—dimethoxyquinazolin-4(3H)-one; 2—(4—(4-benzoylpiperaziny|)phenyl)—5,7—dimethoxyquinazolin-4(3H)~one; 2—(4~(4-(4-f|uorobenzoyl)piperaziny|)phenyl)-5,7—dimethoxyquinazolin- 4(3H)-one; N—(1-(4-(5,7-dimethoxyoxo—3,4-dihydroquinazolin-Z-yl)phenyl)piperidin—4- y|)benzamide; ,7-dimethoxy—Z-(4-(4-picolinoylpiperaziny|)phenyl)quinazolin—4(3H)—one; ,7-dimethoxy~2~(4-(4-nicotinoylpiperazin-1—yl)phenyl)quinazolin-4(3H)-one; 2-(4—(4-isonicotinoylpiperaziny|)phenyI)-5,7-dimethoxyquinazolin—4(3H)— ,7-dimethoxy—Z—(4-(4-(thiophene~2-carbonyl)piperazin-1 - yl)phenyl)quinazolin-4(3H)-one; 4-(5-chloromethyI—1H-pyrazole—4-carbonyl)piperazin-1—y|)pheny|)— ,7-dimethoxyquinazolin-4(3H)~one; ,7—dimethoxy-Z—(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1 - y|)pheny|)quinazolin—4(3H)-one; 2-(4—(4-(2,5-dichlorothiophene—B—carbonyl)piperazin—1—yl)phenyl)-5,7- oxyquinazolin—4(3H)-one; 2—(4-(4-(cyclopropanecarbonyl)piperaziny|)pheny|)-5,7— dimethoxyquinazolin—4(3H)-one; 2-(4—(4—(4-fluorobenzyl)piperazinyl)phenyI)-5,7—dimethoxyquinazolin- 4(3H)-one; 2-(4—(4-benzylpiperazin—1-y|)phenyI)—5,7—dimethoxyquinazolin-4(3H)—one; 2-(4-(4-(2,2,2—trifluoroethyl)piperaziny|)pheny|)quinazolin-4(3H)-one; 2-(4-(4-butylpiperazin—1—y|)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4—acetyI-1,4-diazepany|)phenyI)-5,7-dimethoxyquinazolin-4(3H)- 2-(4—(1,4-diazepany|)pheny|)—5,7-dimethoxyquinazolin-4(3H)—one; ,7—dimethoxy-Z-(4-(4-methyl—1,4-diazepan—1-y|)phenyl)quinazolin-4(3H)- N—(1-(4-(5,7-dimethoxy—4-oxo-3,4—dihydroquinazolin-Z-yl)phenyl)piperidin y|)-N—ethy|acetamide; (3R,5S)—4—acetyI-3,5-dimethylpiperazin-1—y|)pheny|)—5,7- dimethoxyquinazolin—4(3H)—one; 2—(4—((3R,58)—3,5-dimethylpiperazinyl)phenyI)—5,7-dimethoxyquinazolin- 4(3H)—one; 2—(4-(4—acetyl—3-methylpiperazin-1~y|)pheny|)—5,7-dimethoxyquinazolin- N—(1-(4-(5,7—dimethoxyoxo—3,4-dihydroquinazolin-2—yl)phenyl)pyrro|idin- 3-yl)acetamide; 2-(4-(4-isopropylpiperazinyI)phenyl)—8—methoxyquinazolin—4(3H)—one; 2-(4-(4-(2-hydroxyethyl)piperazinyl)phenyI)-5,7-dimethoxyquinazolin- 4(3H)—one; N—(1~(4-(5,7-dimethoxyoxo—3,4-dihydroquinazolin-Z-yl)phenyl)piperidin yl)-N-isopropylacetamide; —chloro—2-(4-(4-isopropylpiperaziny|)pheny|)quinazo|in-4(3H)-one; 2-(4-((3R,5S)—4-isopropyl—3,5-dimethylpiperazinyl)phenyI)-5,7- dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4—(piperidin-4—yl)phenyl)quinazolin-4(3H)—one; ,7—dimethoxy(4-(3-(methylamino)pyrrolidiny|)phenyl)quinazolin— 4(3H)—one; tert-butyl 4-(4-(5,7—dimethoxy-4—oxo-3,4—dihydroquinazolin~2— yl)pheny|)piperidine—1~carboxy|ate; N—(1—(4—(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)pyrrolidin- 3-yl)-N-methylacetamide; 2-(4—(4-(isopropylamino)piperidinyl)phenyl)—5,7-dimethoxyquinazolin- 4(3H)—one; 2-(4-(1-acetylpiperidinyl)phenyl)—5,7—dimethoxyquinazolin—4(3H)—one; methoxy-2~(4—(3-methylpiperazinyl)phenyl)quinazolin-4(3H)-one; N-benzyl—N—(t -(5-(5,7-dimethoxyoxo-3,4—dihydroquinazolin-Z-yl)pyridin~ 2—yl)piperidin-4—yl)acetamide; 2—(6-(4-(benzylamino)piperidinyl)pyridin—3-yI)-5,7-dimethoxyquinazolin- 4(3H)—one; 4-(4-(5,7-dimethoxy-4—oxo-3,4-dihyd roquinazolinyl)phenyl)piperazine-14 carbaldehyde; 2—(4—(2—(1—acetylazetidinyl)ethoxy)-3,5—dimethylphenyE)—5,7— dimethoxyquinazolin-4(3H)-one; 2-(4-(3-(cyclopropylmethylamino)pyrrolidinyl)phenyl)-5,7— dimethoxyquinazolin-4(3H)—one; and ,7—dimethoxy—2-(4-(4—oxopiperidinyl)phenyl)pyrido[2,3-d]pyrimidin- 4(3H)—one, and tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof.

Formula II Methods and Compounds ln n embodiments, the method for inhibiting the expression of, or reducing lL—6 and/or VCAM—1 in a subject, comprises stering a eutically effective amount of at least one compound of Formula ll: Rb3 F|2n1 sz Ntan R83 IQ; V\N Rb5 Rag U/ 6 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q is CH; V is N; U is 0:0; Rc is hydrogen; R32 is hydrogen; Ra1 and R33 are each 01-05 alkyl; sz, Rb3, and Rbe are each hydrogen; Rm is hydrogen; an is selected from sulfonyl, cycle, and aryl; and Rb5 is selected from hydrogen or may be connected with an to form a heterocycie. in some embodiments, the method for inhibiting the expression of, or ng lL-6 and/or VCAM—1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula II, wherein: Q is CH; V is N; U is 0:0; Rc is en; R82 is hydrogen; Ra1 and R33 are each methoxy; sz, Rb3, and Rbe are each hydrogen; Rm is hydrogen; an is selected from esulfonyl, pyridinyl, 4—methylphenyl, and pyridinyl; and Rb5 is selected from hydrogen or may be connected with an to form a heterocycle selected from (2-hydroxymethyl)-1H-pyrrolyl, (2-hydroxyethyl)—1H- yl, 2-(pyrrolidin-1~yl-ylmethyl)-1H-pyrrol—5-yl, 3-(hydroxymethyl)-1H- pyrazol—5-yl, rolidin—1—yl-ylethyl)-1H-pyrrol-5—yl, and 2- ((dimethylamino)methyl)-1H—pyrrolyl.

In certain embodiments, the method for inhibiting the expression of, or reducing IL—6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula II selected from: 2—(4-(dimethylamino)naphthalenyl)—6,7-dimethoxyquinazolin-4(3H)—one; 2-(4—(bis(2—hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3- d]pyrimidin-4(3H)-one; 2-(2—(hydroxymethyI)—1H-indol-5—yl)-5,7-dimethoxyquinazolin-4(3H)—one; 2—(2—(2—hydroxyethyl)—1H—indolyl)—5,7—dimethoxyquinazolin-4(3H)—one; ,7-dimethoxy(2—(pyrrolidinylmethyl)~1H-indolyl)quinazolin—4(3H)— 2—(3-(hydroxymethyl)—1 H—indazol-5~yl)—5,7-dimethoxyquinazolin-4(3H)—one; ,7-dimethoxy—Z-(Z-(Z-(pyrrolidin-’l—yl)ethyI)—1 H—indolyl)quinazolin-4(3H)- 2—(2—((dimethylamino)methyl)—1H-indol—5—yl)-5,7-dimethoxyquinazolin- 4(3H)—one; ,7—dimethoxyoxo-3,4-dihydroquinazolin-2— yl)phenyl)methanesulfonamide; methoxy-Z—(4-(pyridinylamino)phenyl)quinazolin—4(3H)-one; ,7-dimethoxy-Z-(4-(p—tolylamino)phenyl)quinazolin-4(3H)—one; and ,7-dimethoxy—Z-(4-(pyridinylamino)phenyl)quinazolin—4(3H)—one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof. [01 16] Another aspect of the invention provides compounds of Formula II: Rbg Rm sz N,an Ra3 Q V \ \ I Rbs / / N Rb6 R32 U \RC and stereoisomers, tautomers, ceutically acceptable salts, and hydrates wherein: Q and V are independently selected from CH and nitrogen; U is selected from 0:0 and 8:0; R1 and R2 are independently selected from hydrogen, and C1-C6 alkyl; Rc is selected from hydrogen, C1-05 alkyl, and C3-Ce cycloalkyl; Ra1, R82, and R33 are independently selected from hydrogen, C1—Ce alkyl, C1-C6 alkenyl, 01-05 alkynyl, C1-Cs , C3-C5 cycloalkyl, halogen, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and R32 and/or R82 and R33 may be connected to form a cycloalkyl or a heterocycle; Rb; and Rbe are independently selected from hydrogen, n, 01-05 alkyl, C1-Cs alkenyl, 03-06 cycloalkyl, hydroxyl, and amino; Rb3 and Rb5 are ndently selected from hydrogen, halogen, C1-C5 alkyl, 01-05 alkoxy, C3—Cs cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rbg and/or Rb5 and/or Rbs may be connected to form a cycloalkyl or a heterocycle; Rm is selected from hydrogen, C1-C6 alkyl, and C3-C5 cycloalkyl; and an is selected from 01-05 alkyl, C3—C5 lkyl, heterocycle, aryl, alkenyl, acyl, and sulfonyl, wherein Rm and/or an may be connected with Rb3 and/or Rb5 to form a 5- or 6-membered heterocyclic ring, provided that at least one of Ra, R32, and R33 is not hydrogen; and Rm and Rn2 are not both hydrogen, methyl, ethyl, or -CHzCH20H. [01 17] r embodiment provides compounds of Formula II, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, Q is CH; V is N; U is 0:0; Rc is hydrogen; R82 is hydrogen; Ra1 and Rag are each C1-Ce alkyl; Rbg, Rb3, and Rbe are each hydrogen; Rm is hydrogen; Rn2 is ed from sulfonyl, heterocycle, and aryl; and Rb5 is selected from hydrogen or may be connected with an to form a heterocycle.

[O1 18] Another embodiment provides compounds of Formula II, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: Q is CH; V is N; U is C=O; Rc is hydrogen; R82 is hydrogen; Ra1 and R33 are each methoxy; Rb; Rb3, and Rbe are each en; Rn1 is hydrogen; an is selected from methanesulfonyl, pyridinyl, 4-methylphenyl, and pyridinyl; and Rb5 is selected from hydrogen or may be connected with an to form a cycle selected from roxymethyl)—1H-pyrrolyl, (2—hydroxyethyl)—1H- pyrrolyl, 2—(pyrrolldinyl—ylmethyl)—1H-pyrrol—5-yl, 3—(hydroxymethyl)-1H- pyrazolyl, rolidinyl—ylethyl)-1H-pyrrolyl, and 2- ((dimethylamino)methyl)-1H—pyrrol—5—yl.

In one embodiment, compounds of Formula II are selected from: 2—(2—(hydroxymethyl)—1H-indolyl)-5,7-dimethoxyquinazolin-4(3H)—one; 2-(2—(2—hydroxyethyl)-1H-indolyl)—5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy-2—(2-(pyrrolidin-1—y|methyl)-1H~indol-5—yl)quinazolin-4(3H)— 2—(3—(hydroxymethyl)—1H—indazolyl)—5,7—dimethoxyquinazolin-4(3H)—one; ,7—dimethoxy-Z-(Z-(Z-(pyrrolidin-1—yl)ethyl)-1H-indol—5-yl)quinazolin-4(3H)— 2-(2-((dimethylamino)methyl)-1H-indol-5—yl)—5,7—dimethoxyquinazolin- 4(3H)-one; N-(4—(5,7-dimethoxy—4—oxo—3,4—dihydroquinazolin-2— yl)phenyl)methanesulfonamide; ,7—dimethoxy-2—(4-(pyridinylamino)phenyl)quinazolin-4(3H)—one; methoxy-Z-(4-(p-tolylamino)phenyl)quinazolin—4(3H)-one; and ,7-dimethoxy(4-(pyridin—3-ylamino)phenyl)quinazolin—4(3H)-one, and ers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof.

Formula I" Methods and Compounds In certain embodiments, the method for inhibiting the expression of, or reducing lL-6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula lll: sz X(Z)G Ra3 Q v \ \ I Rb5 / ,Nt Rb5 Rag u Rc (III) or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: U is C=O; Q is selected from CR12 and nitrogen; V is selected from nitrogen; Z is selected from unsubstituted C1-C6 alkyl; R12 is selected from 01—06 alkoxy and halogen; Rc is selected from en and C1-06 alkyl; R32 is selected from hydrogen and 01-06 alkoxy; Ra1 and R33 are independently selected from hydrogen, C1-C6 alkyl, C1-Cs alkoxy, halogen, and cycle; Rb2 and Rbs are both en; Rb3 and Rb5 are independently selected from hydrogen and C1-C5 alkyl; X is selected from oxygen and CH2; n is selected from O, 1, 2, 3, or 4; and G is selected from cycle, lkyl, and aryl.

In other embodiments, U is 0:0 in compounds of Formula III that may be used to inhibit the expression of, or reduce lL—6 and/or VCAM—1 in a subject, wherein: Q is selected from CR12 and nitrogen; V is selected from nitrogen; R12 is selected from methoxy and chlorine; Rc is selected from hydrogen and (pyrrolidin—l-yl)propyl; R32 is selected from hydrogen and methoxy; Ra1 and Rae, are independently selected from hydrogen, methyl, chlorine, fluorine, methoxy, isopropoxy, and pyrrolidin—l-yl; Rb2 and Rbe are both hydrogen; Rb3 and Rb5 are independently selected from en and methyl; éXf is selected from imethylpiperidine~1—carboxamide)—4-oxy, 1- acetylpiperidinyloxy, 2-(isoindolin-2—yl)ethoxy, 2-(pyrrolidinyl)ethoxy, 3- (pyrrolidinyl)propoxy, 4—(pyrrolidinyl)butoxy, (4-acetylpiperazinyl)ethoxy, (1 H—imidazol—1—yl)ethoxy, (4-methylpiperazin-1—yl)ethoxy, (piperidinyl)ethoxy, (1-isopropylimidazolidine-2,4-dione)—3-ethoxy, (5—phenylimidazolidine-2,4—dione)— 3—ethoxy, (imidazolidine-2,4—dione)methyl, (2—azepanyl)ethoxy, (2—azetidin yl)ethoxy, N—(azetidinyl)acetamide-1—ethoxy, doline—1,3—dione)-2—ethoxy, pyrrolidin—2—yl)methoxy, (4-isopropylpiperazin—1—yl)methyl, N-isopropyl-N- (piperidinmethyl)acetamide—1~methyl, opropylamino)piperidin—1-yl)methyl, (pyrrolidine-2,5—dione)ethoxy, and (1H-tetrazol-5—yl)methyl.

In certain embodiments, the method for inhibiting the expression of, or reducing lL-6 and/or VCAM—1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula lll selected from: —dimethyl—4—(2—morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin- 1(2H)—one; 2-(3,5-dimethyl(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin— 4(3H)—one; 3-(3,5-dimethyl-4—(2-(4-methylpiperazinyl)ethoxy)phenyI)-6,8- dimethoxyisoquinolin—1(2H)-one; 2—(3,5-dimethyl—4-(2—morpholinoethoxy)phenyl)quinazolin-4(3H)—one; 7-(3,5-dimethyl(2-morpholinoethoxy)phenyl)-2,4-dimethoxy—1,6- naphthyridin-5(6H)-one; ,7~dimethoxy—2-(4-((4-methylpiperazinyl)methyl)phenyl)quinazolin— 4(3H)-one; ,7-dimethoxy-Z—(4-(morpholinomethyl)phenyl)quinazolin—4(3H)—one; 2—(4-((4—ethylpiperazinyl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)— 2—(3,5-dimethyl—4-(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 4—(4-(5,7-dimethoxy—4-oxo—3,4—dihydroquinazolin-2~y|)phenoxy)—N,N- dimethylpiperidine—1—carboxamide; 2-(4-(1-acetylpiperidin-4—yloxy)phenyI)-5,7-dimethoxyquinazolin-4(3H)—one; 2-(4-(2-(isoindolin-2—y|)ethoxy)—3,5-dimethylphenyl)—5,7- dimethoxyquinazolin—4(3H)-one; 2—(3,5-dimethyI—4—(2-(pyrrolidin—1—y|)ethoxy)phenyl)—5-methoxyquinazolin- 4(3H)—one; ,7-dichIoro—2-(3,5-dimethyl—4-(2—(pyrrolidiny|)ethoxy)phenyl)quinazolin- 4(3H)-one; 2—(3,5-dimethyI(3-(pyrrolidinyl)propoxy)phenyI)-5,7—dimethoxy—3-(3- (pyrrolidin-1—yl)propyl)quinazolin-4(3H)—one; 2-(4-(2—(4-acetylpiperazin-1—y|)ethoxy)-3,5—dimethylphenyI)-5,7- dimethoxyquinazolin-4(3H)—one; 2-(1H—imidazoI-1—y|)ethoxy)—3,5—dimethylphenyI)-5,7- dimethoxyquinazolin-4(3H)-one; 2—(3,5-dimethyI—4—(2-(pyrrolidin—1-y|)ethoxy)phenyl)—7-methoxyquinazolin- 4(3H)—one; 2-(3,5—dimethyI(2—(4—methylpiperaziny|)ethoxy)phenyl)—5,7- dimethoxyquinazolin—4(3H)—one; 2-(3,5-dimethyl(2—(piperidiny|)ethoxy)phenyI)-5,7— dimethoxyquinazolin-4(3H)—one; ,7—dimethoxy—2-(3-methyl—4-(2—(pyrrolidin—1-y|)ethoxy)phenyl)quinazolin- 4(3H)-one; 3—(2-(4-(5,7—dimethoxy-4—oxo-3,4-dihydroquinazolin-Z—yI)—2,6— dimethylphenoxy)ethyl)—1-isopropy|imidazolidine—2,4-dione; 2—(3,5-dimethyl(3—(pyrrolidiny|)propoxy)phenyI)-5,7- oxyquinazolin-4(3H)—one; ,7-dimethoxy-2—(4-(2—(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)—one; 2-(3,5—dimethyI(3—(pyrrolidin-1—y|)propy|)phenyl)—5,7- dimethoxyquinazolin-4(3H)—one; 2-(3,5-dimethyl—4-(4-(pyrrolidin—1-y|)butoxy)phenyI)-5,7- dimethoxyquinazolin-4(3H)—one; 2-(3,5-dimethyI—4—(2—(pyrrolidiny|)ethoxy)phenyl)—8—methoxyquinazolin- 4(3H)-one; 3-(2—(4-(5,7-dimethoxyoxo~3,4-dihydroquinazolin-Z-yI)-2,6- dimethylphenoxy)ethyI)—5-pheny|imidazolidine—2,4-dione; 3-(4-(5,7-dimethoxy—4-oxo—3,4-dihydroquinazolin—2—yl)benzyl)imidazolidine- 2,4—dione; 2-(3,5—dimethyl-4—(2—(pyrrolidin-1—yl)ethoxy)phenyl)methoxyquinazolin- 4(3H)—one; -dimethyl—4-(2—(pyrr0lidin-1—yl)ethoxy)phenyl)—5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2—(3,5~dimethyl(2-(pyrrolidin-1—yl)ethoxy)phenyI)fluoro-5—(pyrrolidin yl)quinazolin-4(3H)-one; —chIoro(3,5-dimethyI-4—(2—(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)—one; 2-(4—(2-(azepanyl)ethoxy)-3,5-dimethylphenyl)—5,7-dimethoxyquinazolin- 4(3H)—one; —dimethyl—4-(2—(pyrrolidinyl)ethoxy)phenyl)—5,7-difluoroquinazolin- 4(3H)-one; 2-(4-(2—(azetidin—1-y|)ethoxy)—3,5—dimethylphenyl)-5,7-dimethoxyquinazolin— 4(3H)—one; N-(1-(2-(4-(5,7-dimethoxy—4-oxo—3,4—dihydroquinazolin-Z-yl)~2,6- dimethylphenoxy)ethyl)azetidinyl)acetamide; 2-(3,5-dimethyl(2—(pyrrolidin—‘l -y|)ethoxy)phenyI)-5,7- diisopropoxyquinazolin-4(3H)-one; 8-chloro(3,5-dimethyl(2—(pyrrolidin—1-yl)ethoxy)phenyl)quinazolin- 4(3H)-one; 2—(3,5-dimethyl(2—(pyrrolidinyl)ethoxy)phenyl)-5,7-dimethquuinazolin- 4(3H)-one; 2—(2-(4—(6,8—dimethoxy-1—oxo~1,2-dihydroisoquinolinyl)—2,6- dimethylphenoxy)ethyl)isoindoline-1,3—dione; 2-(3,5-dimethyl—4-(2-(pyrrolidin-1—yl)ethoxy)phenyl)-5,7- diisopropoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2-(2—(4—(5,7—dimethoxyoxo-3,4-dihydroquinazolin-Z-yl)—2,6— dimethylphenoxy)ethyl)isoindoline-1,3-dione; (S)—2-(3,5-dimethyl-4—((5-oxopyrrolidin—2—yl)methoxy)phenyl)-5,7— dimethoxyquinazolin-4(3H)-one; 2—(4-((4-isopropylpiperazinyl)methyl)phenyl)-5,7-dimethoxyquinazolin- N—(1-(4-(5,7—dimethoxyoxo—3,4—dihydroquinazolin-2—yl)benzyl)piperidin yl)-N-isopropylacetamide; 2-(4—((4-(isopropylamino)piperidinyl)methyl)phenyl)—5,7- dimethoxyquinazolin-4(3H)—one; 2-(4-((1H-tetrazolyl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 1-(2—(4-(5,7—dimethoxyoxo-3,4—dihydroquinazolin—2—yl)-2,6— ylphenoxy)ethyl)pyrrolidine-2,5—dione, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

Another aspect of the invention es compounds of Formula lll: sz szie Ra3 Q v \ \ I Rb5 / /N\ Rb6 Rag U Rc (Ill) and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: Q is selected from CR12 and nitrogen; V is selected from CH and nitrogen; U is selected from C=O, 8:0, and 802; Z is selected from unsubstituted C1-Ca alkyl and 01-06 alkyl substituted with one or more groups ed from C1-03 alkyl, C1-C3 alkoxy, cyclopropyl, hydroxyl, amino, and halogen; X is selected from oxygen, nitrogen, sulfur, NR6R7, and CR6R7; n is ed from 0, 1, 2, 3, 4, or 5; G is selected from heterocycle, cycloalkyl, and aryl; R6, R7, and R12 are independently selected from hydrogen, C1—C5 alkyl, C3- C5 cycloalkyl, C1—Cs alkoxy, and n; Rc is selected from hydrogen, 01-06 alkyl, and C3-C6 cycloalkyl; Ra1, R32, and R33 are independently selected from hydrogen, C1-Cs alkyl, 01-05 alkenyl, 01-06 alkynyl, C1-Ce alkoxy, C3-Ce cycloalkyl, halogen, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and R32 and/or Ra;~ and R83 may be connected to form a cycloalkyl or a heterocycle; sz and Rbe are independently selected from hydrogen, halogen, C1—C6 alkyl, C3-C5 cycloalkyl, 01-06 l, yl, and amino; and Rb3 and Rb5 are independently selected from hydrogen, halogen, C1—C6 alkyl, 03-05 cycloalkyl, C1-C5 alkoxy, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rbe may be connected to form a cycloalkyl or a heterocycle; provided that if X = oxygen and n is 3, then Rc is hydrogen; at least one of Ra, R32, and R33 is not en; if R32 or Rae, is chloro, then Ra1 is not hydrogen; X G if Ra1 and R33 are OMe, and Q = CH, then 3 n is not H O 3""ng0 éowfiN/ph ?©;; 0 O I ,or ’ X G if Ra1 and Ra3 are OMe and R82 is hydrogen, then % n is not K/O; and further provided that the compound of a "I is not -dimethyl-4—(2—(pyrrolidin-1—yl)ethoxy)phenyl)—5,7-dimethoxyquinazolin- 4(3H)-one, 2-(2-(4-(5,7-dimethoxyoxo—3,4-dihydroquinazolin-2~yl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3—dione, 3-(3,5—dimethyI(2—(4— methylpiperazin-1—yi)ethoxy)phenyI)-6,8—dimethoxyisoquinolin-1(2H)—one, 2-(4-((4- ethylpiperaziny|)methy|)phenyl)—5,7-dimethoxyquinazolin-4(3H)—one, ,7—dimethoxy-Z—(4-((4-methylpiperazin-1—y|)methyl)phenyl)quinazolin—4(3H)-one, ,7—dimethoxy-Z-(4-(morpholinomethyl)phenyl)quinazolin—4(3H)-one.

Some embodiments provide compounds of Formula ill, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, Q is selected from CR12 and nitrogen; V is selected from en; R12 is selected from C1—C5 alkoxy, and halogen; Rc is selected from hydrogen and 01-05 alkyl; R82 is selected from hydrogen and C1~Ce alkoxy; Ra1 and R33 are independently selected from hydrogen, 01—06 alkyl, C1-C5 alkoxy, halogen, and heterocycle; Rb2 and Rbe are both hydrogen; Rb3 and Rb5 are independently selected from hydrogen and C1-C5 alkyl; X is selected from oxygen and CH2; n is selected from O, 1, 2, 3, or 4; and G is selected from heterocycle, cycloalkyl, and aryl.

Some ments provide compounds of Formula Ill, and isomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: Q is selected from CR12 and nitrogen; V is selected from nitrogen; R12 is selected from methoxy and ne; Rc is selected from hydrogen and (pyrrolidinyl)propyl; R82 is selected from hydrogen and methoxy; Ra1 and R33 are independently selected from hydrogen, methyl, chlorine, ne, methoxy, isopropoxy, and pyrrolidinyl; sz and Rbe are both hydrogen; Rb3 and Rb5 are independently selected from hydrogen and methyl; and %XCZ)"G is selected from imethylpiperidine-1—carboxamide)—4-oxy, 1— acetylpiperidinyloxy, 2—(isoindolinyl)ethoxy, 2-(pyrrolidin—1-yl)ethoxy, 3- (pyrrolidinyl)propoxy, 4-(pyrrolidinyl)butoxy, tylpiperazin-1—yl)ethoxy, (1H-imidazolyl)ethoxy, (4-methylpiperazinyl)ethoxy, (piperidinyl)ethoxy, (1-isopropylimidazolidine~2,4-dione)ethoxy, (5-phenylimidazolidine~2,4—dione)- 3-ethoxy, (imidazolidine—2,4-dione)-3—methyl, (2—azepanyl)ethoxy, tidin yl)ethoxy, N-(azetidin—3—yl)acetamide~1—ethoxy, (isoindoline-1,3-dione)-2—ethoxy, (5-oxopyrrolidinyl)methoxy, (4-isopropylpiperazinyl)methyl, N-isopropyl—N- (piperidin-4—methyl)acetamidemethyl, (4—(isopropylamino)piperidin-1—yl)methyl, (pyrrolidine—2,5~dione)ethoxy, and (1 H-tetrazolyl)methyl.

In one embodiment, compounds of Formula III are selected from: 4—(4~(5,7-dimethoxy—4—oxo-3,4-dihydroquinazolinyl)phenoxy)—N,N- dimethylpiperidine—1-carboxamide; 1—acetylpiperidinyloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2—(4-(2—(isoindolin—2—yl)ethoxy)—3,5-dimethylphenyI)-5,7- dimethoxyquinazolin-4(3H)—one; 2—(3,5-dimethyI—4—(2-(pyrrolidin—1—y|)ethoxy)phenyl)methoxyquinazolin— 4(3H)-one; ,7-dichloro-Z—(3,5-dimethy|~4—(2—(pyrrolidiny|)ethoxy)pheny|)quinazolin- 4(3H)—one; 2-(3,5-dimethyI(3-(pyrrolidin—1~y|)propoxy)phenyI)-5,7-dimethoxy-3—(3- (pyrrolidiny|)propy|)quinazolin-4(3H)-one; 2—(4-(2—(4-acetylpiperazinyl)ethoxy)-3,5-dimethylphenyI)-5,7- dimethoxyquinazolin-4(3H)—one; 2-(4-(2—(1H—imidazoly|)ethoxy)-3,5—dimethylphenyl)—5,7- dimethoxyquinazolin—4(3H)—one; 2-(3,5-dimethyl(2-(pyrrolidiny|)ethoxy)phenyl)—7-methoxyquinazolin- 4(3H)—one; 2-(3,5—dimethyl—4-(2-(4-methylpiperazin—1-y|)ethoxy)phenyl)—5,7— oxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2—(piperidiny|)ethoxy)phenyl)-5,7- dimethoxyquinazolin—4(3H)—one; ,7-dimethoxy-2—(3-methyl(2~(pyrrolidiny|)ethoxy)phenyl)quinazolin- 3-(2—(4—(5,7~dimethoxy-4—oxo—3,4-dihydroquinazolinyi)-2,6- dimethylphenoxy)ethyl)—1—isopropylimidazolidine-2,4-dione; 2—(3,5-dimethyI—4—(3-(pyrrolidin—1—y|)propoxy)pheny|)~5,7- dimethoxyquinazolin—4(3H)-one; ,7-dimethoxy—Z—(4—(2—(pyrrolidin-1—y|)ethoxy)phenyl)quinazolin-4(3H)—one; 2-(3,5-dimethyI—4-(3-(pyrrolidin—1-y|)propyl)phenyI)—5,7- dimethoxyquinazolin—4(3H)~one; 2-(3,5-dimethyl(4—(pyrrolidin—1-y|)butoxy)phenyI)—5,7- dimethoxyquinazolin-4(3H)—one; 2-(3,5—dimethyl(2-(pyrrolidin—1-yl)ethoxy)phenyI)-8—methoxyquinazolin- 4(3H)-one; 3—(2—(4-(5,7-dimethoxy—4-oxo—3,4-dihydroquinazolin-Z—yI)-2,6— ylphenoxy)ethyI)phenylimidazolidine-2,4—dione; 3-(4-(5,7-dimethoxy-4—oxo—3,4—dihydroquinazolin—Z—yl)benzy|)imidazolidine- 2,4—dione; 2—(3,5-dimethyl—4-(2—(pyrrolidin-1—y|)ethoxy)phenyI)—6—methoxyquinazolin- 4(3H)-one; 2—(3,5-dimethyl(2—(pyrrolidinyl)ethoxy)phenyI)-5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2-(3,5—dimethyI—4-(2-(pyrrolidin—1-yl)ethoxy)phenyl)-7~fluoro—5-(pyrrolidin—1- yl)quinazo|in~4(3H)-one; -chIoro—2—(3,5-dimethyI(2—(pyrrolidinyl)ethoxy)phenyl)quinazo|in- 4(3H)—one; 2—(4—(2-(azepan—1—y|)ethoxy)—3,5-dimethylphenyI)—5,7—dimethoxyquinazolin- 4(3H)—one; 2-(3,5-dimethyI—4-(2—(pyrrolidinyl)ethoxy)phenyI)—5,7-difluoroquinazolin- 2-(4-(2-(azetidin-1—yl)ethoxy)—3,5—dimethylphenyI)—5,7~dimethoxyquinazolin- 4(3H)—one; N-(1-(2—(4-(5,7-dimethoxyoxo—3,4-dihydroquinazolin-Z-yl)—2,6- dimethylphenoxy)ethyl)azetidinyl)acetamide; 2—(3,5—dimethyl(2—(pyrrolidinyl)ethoxy)phenyI)—5,7- diisopropoxyquinazolin—4(3H)—one; 8-chloro—2—(3,5-dimethyl-4—(2—(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)—one; 2-(3,5-dimethyl—4~(2~(pyrrolidinyl)ethoxy)phenyl)-5,7-dimethquuinazolin- 4(3H)—one; 2-(2-(4-(6,8—dimethoxy—1—oxo-1,2—dihydroisoquinolinyl)—2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione; 2-(3,5-dimethyl—4-(2—(pyrrolidin—1-yl)ethoxy)phenyl)-5,7— diisopropoxypyrido[2,3—d]pyrimidin-4(3H)—one; (S)-2—(3,5-dimethyl-4—((5—oxopyrrolidin—2-yl)methoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)—one; 2—(4—((4-isopropylpiperazin-1—yl)methyl)phenyl)-5,7-dimethoxyquinazolin- N-(1-(4-(5,7—dimethoxyoxo-3,4—dihydroquinazolinyl)benzyl)piperidin yl)-N-isopropylacetamide; 2-(4—((4—(isopropylamino)piperidinyl)methyl)phenyl)~5,7- dimethoxyquinazolin—4(3H)-one; 2-(4-((1H-tetrazol—5—yl)methyl)phenyl)—5,7—dimethoxyquinazolin—4(3H)-one; 4—(5,7-dimethoxyoxo-3,4—dihydroquinazolin—Z-yl)-2,6- dimethylphenoxy)ethyl)pyrrolidine-2,5-dione, and tautomers, stereoisomers, ceutically acceptable salts, and hydrates thereof.

Formula |V Methods and Compounds In certain embodiments, the method for inhibiting the expression of, or reducing lL—6 and/or VCAM-1 in a subject, ses administering a therapeutically effective amount of at least one compound of Formula lV: 02 / ,NH Rb6 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: U is C=O; V is nitrogen; sz and Rbs are both hydrogen; Rb3 and Rb5 are independently selected from 01-05 alkyl and hydrogen; Q; is selected from 01—05 alkyl and hydrogen; and Q1 and Q3 are independently ed from hydrogen and C1-C6 alkoxy. ln some embodiments, U is C=O in compounds of Formula N that may be used to inhibit the expression of, or reduce lL-6 and/or VCAM-1 in a subject, n V is nitrogen; Rb2 and Rba are both hydrogen; Rb3 and Rb5 are independently selected from methyl and hydrogen; 02 is selected from hydrogen, (4—methylpiperazin-1—yl)methyl, morpholinoethyl, linomethyl, and (pyrrolidin-1~yl)ethyl; and Q1 and 03 are independently selected from hydrogen, benzyloxyethoxy, methoxy, methoxyethoxy, (pyrrolidinyl)ethoxy, phenoxyethoxy, and isopropoxyethoxy. ln one ment, the method for ting the expression of, or reducing IL-6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula lV selected from: 7-(2-(benzyloxy)ethoxy)—5-methoxy-2—(pyridinyl)quinazolin-4(3H)—one; 2—(2,6—dimethylpyridinyl)—5,7—dimethoxyquinazolin-4(3H)~one; 2-(2,6—dimethylpyridinyl)methoxy(2—methoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)—5,7—bis(2-methoxyethoxy)quinazolin—4(3H)-one; 2—(2,6—dimethylpyridinyl)methoxy—5—(2—(pyrrolidin-1 - yl)ethoxy)quinazolin-4(3H)-one; —dimethylpyridinyI)((4—methylpiperazin—1~yl)methy|)quinazolin- 4(3H)-one; 2-(2,6—dimethylpyridin-4—yI)methoxy—7—(2—phenoxyethoxy)quinazolin- 4(3H)—one; -dimethylpyridin—4-yl)methoxy—5-(2—phenoxyethoxy)quinazolin— 4(3H)—one; 2-(2,6—dimethylpyridin—4-yl)methoxy(2—methoxyethoxy)quinazolin- 4(3H)—one; 2-(2,6-dimethylpyridin—4-yI)—5-methoxy—7—(2—(pyrrolidin-1 — y|)ethoxy)quinazolin-4(3H)—one; 2-(2,6-dimethylpyridinyl)—7—(2-isopropoxyethoxy)methoxyquinazolin- 4(3H)—one; 2-(2,6-dimethylpyridin-4—y|)~5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)— 7—(2—(benzyloxy)ethoxy)—2-(2,6-dimethylpyridin-4—yI)—5-methoxyquinazolin- 4(3H)—one; 2—(2,6—dimethylpyridin—4-yl)—6-(2—morpholinoethyl)quinazolin-4(3H)—one; 2-(2—methylpyridinyl)(morpho|inomethyl)quinazolin-4(3H)—one; -methoxy(2-methoxyethoxy)(2-methylpyridiny|)quinazolin—4(3H)- 2-(2,6—dimethylpyridinyI)(2—(pyrrolidinyl)ethy|)quinazolin-4(3H)—one; 2-(2,6-dimethylpyridiny|)(2—isopropoxyethoxy)-7—methoxyquinazolin- 4(3H)—one; and 2—(2,6-dimethylpyridiny|)(2—methoxyethoxy)(2-(pyrrolidin-1— y|)ethoxy)quinazolin—4(3H)-one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or e thereof.

Another aspect of the ion provides compounds of Formula IV: qu \ Rb5 ()fo U,NH Rb6 and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: Q1 is selected from nitrogen and C—Ra1; Q2 is selected from nitrogen and C-Raz; Qg is selected from nitrogen and C-Ras; V is ed from CH and nitrogen; U is selected from C=O and 8:0; Ra1, R32, and R33 are independently selected from hydrogen, C1-Ca alkyl, C1-CG alkenyl, C1-Ce alkynyl, C1-C5 alkoxy, 03-06 cycloalkyl, amino, amide, and heterocycle, n Rai and R32 and/or R32 and R83 may be connected to form a cycloalkyl or a heterocycle; sz and Rbs are independently selected from hydrogen, halogen, 01-06 alkyl, 03-05 cycloalkyl, C1—Ce alkenyl, hydroxyl, and amino; and Rb3 and Rb5 are independently selected from hydrogen, methyl, ethyl, C3- C5 lkyl, C1-C3 alkoxy, and amino, wherein sz and Rb3 and/or Rb5 and Rbe may be connected to form a cycloalkyl or a heterocycle, ed that at least one of Ra, R32, and R33 is hydrogen; if R83 is alkoxy, then Ra1 is not hydrogen; D E" if R82 is y or $0 then Rb3 is not hydrogen; if Rb2, Rb5, and Rbs are hydrogen, then Rbg is not -CH20H; and one of Rb3 and Rb5 is not hydrogen.

Other embodiments provide compounds of Formula N, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: U is C=O; V is nitrogen; sz and Rbs are both hydrogen; Rb3 and Rb5 are independently selected from C1-C5 alkyl and en; 02 is selected from C1-C6 alkyl and hydrogen; and Q1 and Q3 are independently selected from hydrogen and C1-C5 .

Another embodiment es compounds of Formula IV, and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: U is C=O; V is en; Rb2 and Rbe> are both hydrogen; Rbg and Rbs are independently selected from methyl and hydrogen; 02 is selected from hydrogen, (4-methylpiperaziny|)methyl, morpholinoethyl, morpholinomethyl, and (pyrrolidinyl)ethyl; and Q1 and Q3 are independently selected from hydrogen, benzyloxyethoxy, y, methoxyethoxy, (pyrrolidinyl)ethoxy, phenoxyethoxy, and isopropoxyethoxy.

In one embodiment, compounds of Formula N are ed from: 7-(2-(benzyloxy)ethoxy)—5-methoxy—2—(pyridinyl)quinazolin-4(3H)—one; 2-(2,6-dimethylpyridiny|)-5,7—dimethoxyquinazolin-4(3H)—one; 2-(2,6-dimethylpyridinyl)-5—methoxy(2—methoxyethoxy)quinazolin— 4(3H)—one; 2-(2,6-dimethylpyridin—4-y|)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)—one; 2-(2,6—dimethylpyridin—4-y|)methoxy-5—(2—(pyrrolidin-1 — yl)ethoxy)quinazolin-4(3H)—one; 2—(2,6-dimethylpyridin—4-yl)—6—((4—methy|piperazinyl)methyl)quinazolin— 4(3H)—one; 2-(2,6-dimethylpyridin—4-yl)—5-methoxy—7-(2-phenoxyethoxy)quinazolin— 4(3H)—one; 2—(2,6-dimethylpyridinyl)—7-methoxy(2—phenoxyethoxy)quinazolin- 2—(2,6-dimethylpyridin—4-y|)methoxy—5—(2-methoxyethoxy)quinazolin— 4(3H)—one; 2—(2,6-dimethylpyridiny|)methoxy(2—(pyrrolidin-1 - yl)ethoxy)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)—7-(2-isopropoxyethoxy)methoxyquinazolin- 2-(2,6-dimethylpyridiny|)-5,7—bis(2-isopropoxyethoxy)quinazolin-4(3H)— 7—(2—(benzyloxy)ethoxy)—2—(2,6-dimethylpyridin—4-yI)—5—methoxyquinazolin- 4(3H)—one; 2-(2,6-dimethylpyridinyl)(2—morpholinoethyl)quinazolin-4(3H)-one; 2-(2—methylpyridin-4—yl)-6—(morpholinomethyl)quinazolin—4(3H)—one; -methoxy(2-methoxyethoxy)-2—(2—methy|pyridinyl)quinazolin—4(3H)- 2—(2,6-dimethylpyridinyl)—6—(2-(pyrro|idiny|)ethyl)quinazolin-4(3H)—one; 2-(2,6-dimethylpyridinyI)(2-isopropoxyethoxy)-7—methoxyquinazolin— 4(3H)—one; and 2-(2,6-dimethylpyridinyl)—7-(2-methoxyethoxy)(2-(pyrrolidin-1 - yl)ethoxy)quinazolin—4(3H)-one, and tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates Formula V s and Compounds In certain embodiments, the method for inhibiting the expression of, or reducing lL-6 and/or VCAM-1 in a t, comprises administering a therapeutically effective amount of at least one compound of Formula V: R33 Q\ N\ Y—A—D /NH R or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: U is C=O; R82 is ed from hydrogen and amino; Ra1 and R33 are independently selected from hydrogen and C1-Ce alkoxy; Q is CH; Rb3 is selected from hydrogen, C1-C6 alkyl, and C1—C5 alkoxy; Rbg and Rbe are both hydrogen; Y is selected from oxygen; A is C1—C4 alkyl; D may be absent or present, and if present is selected from hydroxy, heterocycle, and NR1R2; and R1 and R2 are independently ed from hydrogen and C1-C5 alkyl.

In some embodiments, the method for inhibiting the expression of, or reducing lL-6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one nd of Formula V, wherein: U is C=O; R32 is selected from hydrogen and amino; Ra1 and R33 are ndently selected from hydrogen and C1—C6 alkoxy; Q is CH; Rb3 is selected from hydrogen, methyl, and methoxy; Rb2 and Rbe are both hydrogen; Y is selected from oxygen; A is ed from methyl and ethyl; D may be absent or present, and if present is selected from y, pyrrolidinyl, and NR1R2; and R1 and R2 are independently selected from hydrogen and acetyl.

In one embodiment, the method for inhibiting the sion of, or reducing lL-6 and/or VCAM-1 in a subject, comprises administering a therapeutically effective amount of at least one compound of Formula V selected from: 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin—4(3H)-one; 2-(3-(2-hydroxyethoxy)phenyl)—5,7-dimethoxyquinazolin-4(3H)—one; 2-(3—(2—hydroxyethoxy)—5—methylphenyl)—5,7-dimethoxyquinazolin—4(3H)— methoxy—2-(3—methoxy(2—(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)—one; N—(2-(3-(5,7-dimethoxyoxo-3,4-dihydroquinazolin-Z—yl)-5— methoxyphenoxy)ethyl)acetamide; 2-(3,5-dimethoxyphenyl)—6—(pyridin—4-ylamino)quinazolin-4(3H)—one; and ,7-dimethoxy-Z-(B—methoxyphenyl)quinazolin-4(3H)-one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

Another aspect of the invention provides compounds of Formula V: R83 Q\ N\ Y—A—D / ,NH Rb6 R82 U and stereoisomers, ers, pharmaceutically acceptable salts, and hydrates thereof, wherein: Q is selected from CR6 and nitrogen; U is selected from C=O and 802; Y is selected from oxygen, nitrogen, sulfur, NR6, CR5R7; A is C1—C4 alkyl, wherein the alkyl chain may be connected to Y, D, Rb3 and/or Rb5 to form a cycloalkyl or heterocycle; D may be absent or t, and if present is selected from —OR1, —NR1R2; R1 and R2 are independently selected from en, C1-C5 alkyl, 03-06 cycloalkyl, sulfonamide, carboxamide, acyl, and nitrile, wherein R1 and R2 may be connected to form a cycloalkyl or a heterocycle; R5 and R7 are independently selected from hydrogen, C1-Ce alkyl, 03—06 cycloalkyl, C1-Ca alkoxy, yl, and halogen; Ra1, R82, and R83 are independently selected from en, C1-Ce alkyl, C1-Cs alkenyl, C1—Cs alkynyl, C1-Cs alkoxy, C3-C5 cycloalkyl, halogen, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and R32 and/or R32 and R33 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rbs are independently selected from hydrogen, halogen, 01-06 alkyl, and 03—06 cycloalkyl; and Rbg is ed from hydrogen, halogen, C1—C6 alkyl, Cg-Ce lkyl, C1— 05 alkoxy, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rbe may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra, R82, and R83 is not hydrogen; if R31 and R33 are both hydrogen, and Y = nitrogen, then R32 is not hydrogen, -OAc, or —OMe; and further provided that the compound of Formula V is not 2-(3,5-dimethoxyphenyl)-5,7—dimethoxyquinazolin—4(3H)—one or 2-(3,5—dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)—one.

Some ments e compounds of Formula V and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates f, wherein: U is C=O; R32 is selected from hydrogen and amino; Ra1 and R33 are independently selected from hydrogen and C1-CB alkoxy; Q is CH; Rb3 is selected from hydrogen, C1-C5 alkyl, and C1—Cs alkoxy; sz and Rbe are both hydrogen; Y is selected from oxygen; A is C1-C4 alkyl; D may be absent or present, and if present is selected from hydroxy, heterocycle, and NR1R2; and R1 and R2 are independently selected from hydrogen and C1-C5 alkyl.

Some ments provide compounds of Formula V and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof, wherein: U is C=O; R32 is selected from hydrogen and amino; Ra1 and R33 are ndently selected from hydrogen and 01-06 ; Q is CH; Rb3 is selected from hydrogen, methyl, and methoxy; Rb2 and Rbs are both hydrogen; Y is selected from oxygen; A is selected from methyl and ethyl; D may be absent or present, and if present is selected from hydroxy, pyrrolidin-1—yl, and NR1R2; and R1 and R2 are independently selected from hydrogen and acetyl.

In one embodiment, compounds of Formula V are selected from: 2-(3-(2-hydroxyethoxy)phenyl)—5,7—dimethoxyquinazolin~4(3H)-one; 2-(3-(2-hydroxyethoxy)-5—methylphenyl)—5,7—dimethoxyquinazolin—4(3H)- ,7-dimethoxy-Z-(3—methoxy(2—(pyrrolidin~1—yl)ethoxy)phenyl)quinazolin- 4(3H)—one; N-(2-(3-(5,7-dimethoxy-4—oxo-3,4-dihydroquinazolin-Z-yl)—5— methoxyphenoxy)ethyl)acetamide; 2-(3,5-dimethoxyphenyl)-6—(pyridinylamino)quinazolin—4(3H)—one; and ,7-dimethoxy-Z-(S—methoxyphenyl)quinazolin-4(3H)—one, and tautomers, isomers, pharmaceutically acceptable salts, and hydrates thereof.

Pharmaceutical compositions of the invention comprise at least one compound of Formula I, ll, lll, IV, V, or tautomer, stereoisomer, pharmaceutically able salt or hydrate thereof formulated together with one or more ceutically acceptable carriers. These ations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, uscular, intradermal, or intravenous) stration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented in te units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the invention as powder or granules; as a solution or a suspension in an aqueous or ueous liquid; or as an oil-in— water or water-in—oil on. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into ation at least one compound of the invention as the active compound and a carrier or ent (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the ent. The carrier may be a solid or a liquid, or both, and may be ated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound. Other pharmacologically active substances may also be present including other compounds. The formulations of the invention may be prepared by any of the well known techniques of pharmacy consisting ially of admixing the components.

For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium ate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the ion as described herein and al pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, ol, ethanol, and the like, to thereby form a solution or suspension. In l, suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the invention with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the ion, which may be optionaily combined with one or more accessory ingredients. Compressed s may be prepared by compressing, in a suitable machine, at least one nd of the invention in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the invention is moistened with an inert liquid t.

Formulations suitable for buccal (sub—lingual) administration include lozenges comprising at least one compound of the invention in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the invention suitable for parenteral administration comprise sterile aqueous preparations of at least one comound of Formula I, II, III, IV, V, or ers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are approximately ic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be ed by means of subcutaneous, uscular, or intradermal injection. Such preparations may conveniently be prepared by admixing at least one compound described herein with water and ing the resulting solution sterile and ic with the blood. Injectable compositions according to the invention may contain from about 0.1 to about 5% w/w of the active compound.

Formulations suitable for rectal administration are presented as unit- dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting e.

Formulations suitable for topical application to the skin may take the form of an ointment, cream, , paste, gel, spray, aerosol, or oil. Carriers and ents which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound (i.e., at least one compound of Formula I, ll, lll, IV, V, or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof) is lly present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5 to about 2%.

The amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing le may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 pg to about 1000 mg. In another embodiment, intermittent administration, such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows the administration of the active ients simultaneously, in theory producing a synergistic effect. in accordance with standard dosing regimens, physicians will readily determine optimum s and will be able to readily modify administration to achieve such dosages.

A therapeutically ive amount of a compound or ition disclosed herein can be measured by the therapeutic effectiveness of the compound. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being d, and the nd being used. In one embodiment, the therapeutically effective amount of a disclosed nd is sufficient to establish a maximal plasma concentration.

Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to cepted practices.

Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Report‘s 219-244 (1966) and Table 1 for Equivalent e Area Dosage Factors).

Table 1. Equivalent Surface Area Dosage Factors Mouse Rat Monkey Dog Human (20 g) (150 g) (3-5 k9) (8 kg) (60 k9) Mouse Monkey Human The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED5O with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the l condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

In one embodiment, a compound of Formula I, II, Ill, IV, V or a tautomer, stereoisomer, ceutically acceptable salt or hydrate thereof, is administered in combination with another eutic agent. The other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the invention alone. The therapeutic agent can be, for example, a statin; a PPAR t, e.g., a thiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; a bile—acid reuptake inhibitor; a cholesterol absorption inhibitor; a cholesterol synthesis inhibitor; a cholesteryl ester er n (CETP), an ion—exchange resin; an antioxidant; an inhibitor of AcleoA cholesterol acyltransferase (ACAT tor); a tyrophostine; a sulfonylurea-based drug; a biguanide; an alpha—glucosidase tor; an apolipoprotein E regulator; a A reductase inhibitor, a microsomal triglyceride transfer protein; an LDL- lowing drug; an HDL-raising drug; an HDL enhancer; a tor of the apolipoprotein A—IV and/or apolipoprotein genes; or any cardiovascular drug.

In another embodiment, a compound of Formula I, II, III, IV, V or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof, is administered in combination with one or more anti-inflammatory agents. Anti- inflammatory agents can include immunosuppressants, TNF inhibitors, corticosteroids, non—steroidal anti-inflammatory drugs s), disease- ing anti—rheumatic drugs S), and the like. Exemplary anti- inflammatory agents e, for example, prednisone; prenisolone (Medrol®), triamcinolone, methotrexate (Rheumatrex®, Trexall®), hydroxychloroquine (Plaquenil®), sulfasalzine (Azulfidine®), leflunomide (Arava®), etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), rituximab an®), abatacept ia®), interleukin-1, anakinra (KineretT'V'), ibuprofen, ketoprofen, fenoprofen, naproxen, aspirin, acetominophen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, lac, ac, mic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, butazone, oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine.

Therapeutic Methods In one embodiment, a method of treating or preventing cardiovascular and inflammatory diseases and related disease states, terized by altered expression of markers of inflammation such as |L-6 and/or VCAM-1 proliferation, comprises administering to a subject (e.g., a mammal, such as e.g., a human) a therapeutically effective amount of at least one compound of the invention, Le, a compound of Formula I, II, III, IV, V, or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof. In another embodiment, at least one compound of the invention may be administered as a ceutically acceptable composition, sing one or more compounds of the invention and a pharmaceutically acceptable carrier.

In one embodiment, the inflammatory diseases and related disease states are those where inhibition of lL-6 and/or VCAM-1 proliferation is desirable.

In some embodiments, the methods of the invention comprise administering at least one compound of the invention to a subject, such as a human, as a preventative measure against cardiovascular and inflammatory diseases and related disease states, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s).

In one embodiment, at least one compound of the invention is administered as a preventative measure to a subject, such as a human, having a genetic predisposition to vascular and inflammatory diseases and related disease states, such as, for e, familial hypercholesterolemia, familial combined hyperlipidemia, sclerosis, a dyslipidemia, a dyslipoproteinemia, arthritis, cancer, multiple sclerosis, or Alzheimer's disease. in another embodiment, at least one nd of the present invention is administered as a preventative measure to a subject, such as a human, having a non-genetic predisposition to a e including a cardiovascular disease or an inflammatory disorder. Examples of such nongenetic predispositions include cardiac bypass surgery and PTCA (which can lead to restenosis), an accelerated form of atherosclerosis, diabetes in women, (which can lead to polycystic ovarian disease), and cardiovascular disease (which can lead to impotence). Accordingly, compositions of the invention may be used for the prevention of one disease or disorder and concurrently treating another (e.g., prevention of polycystic ovarian e while ng diabetes; prevention of impotence while treating a cardiovascular disease).

Angioplasty and open heart surgery, such as ry bypass surgery, may be ed to treat cardiovascular diseases, such as atherosclerosis. These surgical procedures entail using invasive surgical devices and/or implants, and are associated with a high risk of restenosis and thrombosis.

Accordingly, the compounds of the invention may be used as coatings on surgical devices (e.g., ers) and implants (e.g., stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used in the treatment of cardiovascular diseases.

In r ment, the compounds of the invention may be used for the prevention of one disease or disorder while concurrently treating another (e.g., prevention of polycystic n disease while treating diabetes; prevention of impotence while treating a cardiovascular disease).

EXAMPLES The invention is further illustrated by the following non-limiting examples, wherein the ing abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

AcOH = acetic acid BINAP = 2,2’-bis(diphenylphosphino)—1,1’-binaphthyl Boc = N-tert—butoxycarbonyl TBDMS = tert-butyldimethylsiiyl dba = dibenzylidene acetone DCM = dichloromethane DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = ylsuifoxide EDCI = 1-ethy|—3—(3’-dimethylaminopropyi)carbodiimide EtOH = ethanol EtOAc = ethyl acetate IBX = 1 ,2—benziodexol-3(1H)-one-1—hydroxyoxide MeOH = methanol HOBt = N-hydroxybenzotriazoie THF = tetrahydrofuran TEA = triethyiamine p~TSA = enesulfonic acid TBAF = tetrabutylammonium fluoride DMA = N,N-dimethy|acetamide H = utylaluminum hydride TPAP = tetrapropylammonium perruthenate NMO = N-methylmorpholine N-oxide DDQ = 2,3-dicyano-5,6-dichioro-parabenzoquinone DME = 1,2-dimethoxyethane TFA = trifluoroacetic acid DPPF = 1,1’-bis(diphenylphosphino)ferrocene Pd(OAc)2 = paliadium(|l) acetate Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0) Example 1. Preparation of 2—(4-(4-(2-hydroxyethyl)piperazin—1-yl)phenyl)—5,7— dimethoxyquinazolin-4(3H)—one (2) .mfiqordfi w N/\/OH cho3, DMF .mmocrNH OCH3O 1 OCH3O 2 To a solution of 5,7-dimethoxy(4-(piperazin yl)phenyl)quinazolin—4(3H)—one (1) (0.68 mmol) in DMF (8 mL) was added potassium carbonate (0.68 mmol) and 2-bromoethanol (0.68 mmol). The resulting solution was stirred at room temperature overnight. Then, the mixture was diluted with water, ted with EtOAc, washed with brine, dried over anhydrous NaZSO4, filtered, and concentrated in vacuo to afford 2. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHClg/MeOH/concentrated NH4OH in CHgClg, The product was further purified by reverse—phase chromatography, g with 10% to 90% CH3CN in H20, to afford the title compound (0.025 g, 9%). 1H NMR (300 MHz, DMSO-ds): 6 11.45 (s, 1H), 8.08 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 9.1 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 4.30- 4.55 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43-3.67 (m, 2H), 3.10-3.43 (m, 7H), 2.77—3.04 (m, 1H), 2.31—2.64 (m, 2H). ESl MS m/z 411 .

Example 2. Preparation of 2—(4—(4-butylpiperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)—one (7) OCH3O 6 H3C0 N\ , p-TSOH, DMA To a solution of 1-(N—butyl)—piperazine (3) (7.03 mmol) in DMF (8 mL) was added 4-fluorobenzaldehyde (4) (8.43 mmol) and potassium carbonate (8.43 mmol). The resulting solution was heated to 120 °C for 5 hours and diluted with water. The solution was extracted with EtOAc, washed with water, brine, dried over anhydrous N32804, filtered, and concentrated in vacuo. The material was purified by flash tography on silica gel to afford 4—(4— butylpiperazinyl)benzaldehyde (5).

To a solution of 2-amino-4,6—dimethoxybenzamide (6) (1.19 mmol) in DMA (1 0 mL) was added 4—(4-butylpiperazin-1—y|)benzaldehyde (5) (1.09 mmol), NaH803 (1.30 mmol), and p-TsOH (0.10 mmol). The resulting solution was heated to 155 °C for 4 hours and cooled to room temperature. The solution was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous N32804, filtered, and trated in vacuo. The material was purified by flash tography on silica gel eluting with 10% to 50% of 922721 CHCIg/MeOH/ concentrated NH4OH in CH20|2,tO afford the compound 7 (0.06 g, 13%). 1H NMR (300 MHz, DMSO-ds):611.76(s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.17-3.42 (m, 4H), 2.39—2.58 (m, 4H), 2.23~2.37 (m, 2H), .56 (m, 2H), 1.26-1.37 (m, 2H), 0.84- 0.94 (m, 3H). APCI MS m/z 423 [M+H]+.

Example 3. Preparation of 2-(4-(1—acetylpiperidinyl)phenyl)—5,7— dimethoxyquinazolin~4(3H)—one (13) . Boc Br \ N,Boc H3C0 N \ H3C H3CO ot Q K2C03,PdC12(dppf) Nx NH H36 l3 NH + KO DMF OCHgO H3C CH3 OCH3O 8 9 10 Pd/C, H2, EtOH H3C0 N\ 4M HC] in dioxane OCH30 11 NH NJKCH3 H3CO N\ acetyl chloride H3CO N\ NH Et3N, CHZCIZ mm; OCH3O 12 OCH3O 13 A solution of romophenyl)-5,7-dimethoxyquinazolin-4(3H)—one (8) (3.23 mmol), K2C03 (9.69 mmol), dppf) (0.32 mmol) and tert—butyl 4—(4,4,5,5~tetramethyl-1,3,2—dioxaborolan-Z-yl)—5,6—dihydropyridine-1(2H)— carboxylate (9) (3.23 mmol) in DMF (50 mL) was heated to 110 °C overnight. The resulting solution was concentrated in vacuo and the material was purified by flash chromatography on silica gel to give tert-butyl 5,7-dimethoxyoxo-3,4- dihydroquinazolin—Z—yl)phenyl)—5,6-dihydropyridine-1(2H)-carboxylate (10).

A solution of tert-butyl 4—(4-(5,7-dimethoxy—4-oxo-3,4- dihydroquinazolinyl)phenyl)—5,6-dihydropyridine-1(2H)-carboxylate (10) (0.34 mmol) in EtOH (10 mL) and HOAc (5 mL) was purged with nitrogen and % Pd/C (0.016 g) was added. The mixture was stirred under 1 atmosphere of hydrogen overnight. Then, the solution was filtered through Celite, with MeOH washings, and the te was concentrated in vacuo. The material was purified by flash chromatography on silica gel to afford tert—butyl 4-(4-(5,7—dimethoxyoxo- 3,4-dihydroquinazolin-2~yl)phenyl)piperidine—1-carboxylate (11).

To a solution of felt—butyl 4-(4-(5,7—dimethoxyoxo—3,4- dihydroquinazolin—2-yl)phenyl)piperidine-1~carboxylate (11) (0.45 mmol) in 1,4- dioxane (2 mL) was added 4 M HCl in 1,4—dioxane (1 mL). The ing solution was d at room temperature for 5 hours. Then, the mixture was concentrated in vacuo and and the resulting material was purified by flash chromatography on silica gel to afford compound 5,7-dimethoxy(4-(piperidinyl)phenyl)quinazolin- 4(3H)—one (12).

To a solution of 5,7~dimethoxy—2-(4—(piperidinyl)phenyl)quinazolin- 4(3H)-one (0.16 mmol) in CH2Cl2 (10 mL) was added Et3N (0.32 mmol) and acetyl chloride (0.17 mmol). The resulting solution was stirred at 0 °C overnight. The on was concentrated in vacuo, basified with NaHCO3, extracted with CHzclg, and washed with water and brine. The material was dried (Na2804), ed, and concentrated to afford the title nd 13 (0.020 g, 30%). 1H NMR (300 MHz, DMSO-d5)3511.93(8, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 4.42-4.64 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.06-3.21 (m 1H), 2.77294 (m, 1H), 2.54-2.68 (m, 1H), 2.03 (s, 3H), 1.73-1.91 (m, 2H), 1.56—1.73 (m, 1H), 1.36-1.56 (m, 1H), 1.06—1.36 (m, 1H). ESI MS m/z 408 [M+H]+.

Example 4. Preparation of 2-(4-(3-(cyclopropylmethylamino)pyrrolidin—1- yl)phenyl)~5,7-dimethoxyquinazolin-4(3H)—one (15) H3CO\@P/©/N >—CHo Pt02 H2, EtOH H3CO\©::/©NH 0 15 A suspension of 2—(4-(3-aminopyrrolidinyl)phenyl)-5,7- dimethoxyquinazolin—4(3H)—one (14) (0.21 mmol) in ethanol (30 mL) was treated with PtOz (0.050 9) followed by cyclopropanecarbaldehyde (0.100 mL). The reaction was d under 1 atmosphere of hydrogen for 24 hours, filtered through Celite, with ethanol , concentrated, and purified by flash chromatography on silica gel, eluting to afford the title compound 15.

Example 5. Preparation of 2~(4-(2-(1-acetylazetidin—3-yl)ethoxy)—3,5~ dimethylphenyl)—5,7—dimethoxyquinazolin-4(3H)-one (19) \n/ "WK /0 O la: 18 O N Pd(OH)2 / C HCI Hillj O fivtkr Ph E N/ DMF3 EtOH, conc HCl o o To a solution of N—(1~benzhydryI-azetidinyl)—acetamide (16) (3.57 mmol) in ethanol (20 mL) were added palladium hydroxide on carbon (20 wt%, 0.20 g) and concentrated HCI (0.6 mL). The reaction mixture was hydrogenated at 50 psi at 40 °C for 2 hours, then filtered and washed with methanol (50 mL). The filtrate was collected and the solvent was evaporated, to give N-azetidinyl—acetamide (17).

To a suspension of N—azetidinyl—acetamide (17) (1.99 mmol) and 2-[4-(2-bromo-ethoxy)~3,5—dimethyI-phenyl]—5,7—dimethoxy—3H-quinazolinone (18) (1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under en. The solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was ed off. The aqueous layer was extracted with ethyl acetate (2X100 mL). The organic phase was dried over ous NaZSO4 and concentrated. The crude compound was purified by the Simpliflash system (0-5% 7 N a in methanol and CH2C|2 as eluent) to give the title compound 19 as a white solid.

Example 6. ation of 2-(2,6—dimethylpyridinyl)(2—isopropoxyethoxy)-7— methoxyquinazolin-4(3H)-one (23) / N / N F N\ l mm\ NaH F N \ o/\/OH DMF, rt, 16 h NH F O Ao/VO O 21 NaOMe /O N\ DMF, 60 0c, 72 h ADA/O O To a solution of 2—isopropoxy ethanol (21) (57.0 mmol) in anhydrous DMF (10 mL) was added a sodium hydride (60 % suspension in mineral oil, 28.54 mmol) in small portions at room temperature under nitrogen. After the addition, the reaction mixture was d at room temperature for 30 minutes.

Then, 2—(2,6—dimethyl-pyridinyl)—5,7-difluoro—3H-quinazolinone (20) (2.85 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to room temperature and saturated NH4C| solution was added. The product was ted with ethyl acetate (3XZ00 mL). The combined organic layer was washed with water, brine, dried over anhydrous Na2804, and ated to give crude product (22) as a white solid. 2—(2,6—Dimethyl—pyridin—4-yl)f|uoro—5—(2-isopropoxy-ethoxy)—3H— olinone (22) (960 mg, 2.58 mmol) was taken up in anhydrous DMF (10 mL). Sodium methoxide (25% solution in methanol, 12.9 mmol) was added.

After the addition, the reaction mixture was stirred at 60 °C for 72 hours. The reaction mixture was cooled to room temperature, and quenched with saturated solution of NH4CI. The product was extracted with ethyl e (BXZOO mL). The combined organic layer was washed with water, brine, dried over , and evaporated to give crude product. The crude compound was purified by preparative HPLC, to give the title compound 23 as a white solid.

Example 7. Preparation of 2—(4—((3R,5S)~4~Acetyl—3,5-dimethylpiperazin-1— yl)phenyl)-5,7—dimethoxypyrido[2,3-d]pyrimidin~4(3H)—one I/ NH /o o To a solution of 4-fluoro-benzaldehyde (3.0 g, 0.024 mol) and 1—(2,6- dimethyl-piperazin—1~yl)-ethanone (3.0 g, 0.019 mol) in anhydrous DMF (15 mL) was added potassium carbonate (6.6 g, 0.048 mol). The reaction mixture was heated to 130 °C for 32 hours. The DMF was d and the residue was purified by column tography (silica gel 230—400 mesh; eluting with 2:1 ethyl e and dichloromethane) to give 4-(4—acetyl-3,5-dimethyl-piperazinyl)- benzaldehyde as light yellow solid (2.31 g, 46.2%).

A mixture of 2-amino—4,6-dimethoxy—nicotinamide (0.25 g, 1.26 mmol), 4-(4—acetyl—3,5—dimethyl-piperazinyl)-benzaldehyde (0.43 g, 1.64 mmol), p—toluenesulfonic acid drate (0.53 mg, 2.77 mmol) and sodium bisulfite (0.45 g, 2.52 mmol) in N,N-dimethylacetamide (5.0 mL) was stirred at 135 °C under N2 for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The itate was filtered and the solid was rinsed with water and dried over NaZSO4. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 2.5% methanol in dichloromethane) to afford the title compound as yellow solid. Yield: 90 mg (16.3%). MP 279-2798 °C. 1H NMR (400 MHz, CDCl3): 810.18(s, 1H), 8.14 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.20 (s, 1H), 4.78 (bs, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 3.70 (d, J: 12.0 Hz, 2H) 3.11 (d, J: 10 Hz, 2H), 2.18 (s, 3H), 1.40 (bs, 6H).

Example 8. Preparation of 2—(4-(4—Hydroxypiperidinyl)phenyl)-5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)—one O O A mixture of 2-amino—4,6-dimethoxy—nicotinamide (0.60 g, 3.0 mmol), 4-(4-hydroxy—piperidinyl)-benzaldehyde (0.81 g, 3.9 mmol), p- toluenesulfonic acid monohydrate (1.25 g, 6.6 mmol) and sodium bisulfite (1.06 g, 6.0 mmol) in N,N-dimethylacetamide (8.0 mL) was stirred at 135 °C under N2 for 16 hours and then cooled to room ature. The mixture was trated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The precipitate was filtered and the solid was rinsed with water and air-dried. The crude solid was purified by column chromatography a gel 230-400 mesh; eluting with 4% methanol in dichloromethane) to afford the title compound, as a yellow solid. Yield: 0.29 g (25.2%). MP 284-286 °C. 1H NMR (400 MHz, DMSO—da):812.0'9(s, 1H), 8.12 (d, J: 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.32 (s, 1H), 4.73 (d, J = 4.4 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.72 (m, 3H), 3.05 (m, 2H), 1.80 (m, 2H), 1.43 (m, 2H). MS (ES+) m/z: 383.06 (M+1).

Example 9. Preparation of 2-(4-((3R,5S)—4-Acetyl-3,5-dimethylpiperazin—1~ yl)phenyl)—5-methoxy(2-methoxyethoxy)quinazolin—4(3H)-one ; 0 \0/\/O Nfl <17)" /0 o To a stirred on of 2-aminc-4,6-difluoro-benzamide (0.66 g, 3.84 mmol) and 4—(4—acetyl~3,5-dimethyl-piperazinyl)—benzaldehyde (1.00 g, 3.84 mmol) in methyl acetamide (20 mL), was added sodium hydrogen sulfite (58.5 wt%, 1.04 g, 5.76 mmol) and p-toluenesulfonic acid monohydrate (0.88 g, 4.61 mmol) and the reaction mixture was stirred at 115 °C for 16 hours.

The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off, to give 2-[4—(4—acetyl-3,5-dimethyl—piperazinyl)-phenyl]—5,7- difluoro-3H-quinazolin—4—one as a yellow solid, which was used in the next step t further cation.

To a solution of 2-[4-(4—acetyl—3,5—dimethyl-piperazinyl)—phenyl]- ,7—difluoro~3H-quinazolinone (0.66 g, 1.60 mmol) in DMF (10 mL), a solution of sodium methoxide in methanol (25 wt%, 3.5 mL, 16.0 mmol) was added and the reaction mixture was stirred at room ature for 16 hours. Water was added, acidified to pH approximately 4-5 with acetic acid, and the precipitated solid was filtered and dried under vacuum to give crude compound, which was further purified by column chromatography (silica gel 230—400 mesh; eluting with 2% methanol solution in dichloromethane) to yield 2—[4—(4-acetyl-3,5-dimethyl- piperazinyl)—phenyl]-7—fluoro—5-methoxy-3H-quinazolin—4—one as a light yellow solid.

To a solution of 2-methoxy—ethanol (1.00 g, 13.4 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.50 g, 12.5 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2-[4-(4-acetyl-3,5— dimethyl-piperazinyl)-phenyl]fluoro—5-methoxy-3H-quinazolin—4—one (0.57 g, 1.34 mmol) and the reaction mixture was stirred at 85 °C for 24 hours. Water was added. The mixture was ied to pH approximately 4—5 with acetic acid, and the precipitated solid was filtered to give crude product, which was purified by column chromatography a gel 230-400 mesh; eluting with 2% methanol in dichloromethane). The resulting mixture was ed by preparative HPLC to obtain the title compound as a white solid. Yield: 0.140 g (23.2%). MP 225-227°C. 1H NMR (400 MHz, CDClg): 6 8.10 (d, J: 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.50 (bs, 1H), 4.23 (m, 2H), 4.14 (bs, 1H), 3.84 (s, 3H), 3.81 (m, 2H), 3.69 (m, 2H), 3.32 (s, 3H), 2.99 (bs, 2H), 2.07 (s, 3H), 1.25 (bs, 6H). MS (ES) m/z: 481.11 (M*+1).

Example 10. ation of 2-(4-(4—lsopropylpiperazinyl)phenyl)—5,7- dimethoxyquinazolin-4(3H)—one A mixture of 4-fluorobenzaldehyde (0.242 g, 1.95 mmol), 1- isopropylpiperazine (0.335 mL, 2.34 mmol), and K2003 (0.323 g, 2.34 mmol) in DMF (2.44 mL) was heated at 120 °C overnight. The mixture was diluted with EtOAc (200 mL), washed with 10% aqueous LiCI (3X75 mL) and brine (75 mL), dried over Na2804, and filtered. The volatiles were removed under vacuum to yield 4-(4-lsopropylpiperazinyl)benzaldehyde (0.504 g) as an orange solid, which was used without further purification.

A mixture of 2—amino-4,6-dimethoxybenzamide (0.100 g, 0.510 mmol), aldehyde from above (0.118 g, 0.510 mmol), NaHSOs (94%, 0.0565 g, 0.510 mmol), and p—TsOHoHZO (0.0097 g, 0.051 mmol) in DMA (3.40 mL) was heated at reflux for 1 hour. The mixture was diluted with EtOAc (250 mL), washed with 10% aqueous LiCl (3X75 mL) and brine (75 mL), dried over Na2804, filtered and trated under . The resulting residue was purified over silica gel (12 g, CH2Cl2/MeOH) and the t was freeze—dried from MeCN/HZO to provide the title nd (0.0632 g, 30%) as a yellow solid. 1H NMR (300 MHz, DMSO-de):611.74(s, 1H), 8.09 (d, J = 9.05 Hz, 2H), 7.00 (d, J = 9.05 Hz, 2H), 6.68 (d, J = 2.31 Hz, 1H), 6.47 (d, J = 2.31 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.31-3.24 (m, 4H), 2.74—2.63 (m, 1H), 2.61-2.53 (m, 4H), 1.01 (d, J = 6.52 Hz, 6H).

Example 11. Preparation of 2—(4-(4-Acetylpiperazin—1—y|)phenyl)—5,7— dimethoxyquinazolin-4(3H)-one Following the procedure described for Example 10, 4-(4—acetylpiperazin—1-yl)benzaldehyde was made from 1-acetylpiperazine and isolated as an orange oil in 67% yield. Following the procedure described for Example 10, the title compound was made from 4—(4—acetylpiperazin—1- yl)benzaldehyde and ng for 5 hours. The title compound was isolated as a yellow solid in 20% yield. 1H NMR (300 MHz, DMSO-de): 6 11.76 (s, 1H), 8.11 (d, J = 8.97 Hz, 2H), 7.03 (d, J = 8.97 Hz, 2H), 6.69 (d, J = 2.26 Hz, 1H), 6.47 (d, J = 2.26 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.62—3.53 (m, 4H), 3.41-3.25 (m, 4H), 2.05 (s, 3H); MS (ESI) m/z 409 [022H24N4O4+H]+. e 12. Preparation of 5,7-Dimethoxy(4-(piperazinyl)phenyl)quinazo|in- 4(3H)—one A mixture of cetylpiperazinyl)benzaldehyde (1.34 g, .77 mmol) and 2-amino-4,6—dimethoxybenzamide (1.03 g, 5.24 mmol) in DMA (30 mL) was treated with p-TsOH (0.100 g, 0.524 mmol) and NaHS03 (0.578 g, .55 mmol). The mixture was heated at 155 °C for 6 hours, cooled to room temperature, diluted with water (400 mL), and filtered to give brown solids. The filtrate was extracted with EtOAc (3X100 mL), concentrated, and combined with the brown solids from the filter cake. The combined solids were purified by silica gel chromatography, eluting with 92:7:1 MeOH/concentrated NH4OH to afford 2-(4-(4-acetylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one as a yellow solid (1.9 g, 90%).

A mixture of 2~(4—(4-acetylpiperazinyl)phenyl)—5,7- dimethoxyquinazolin-4(3H)-one (1.93 g, 4.7 mmol) and 2 M HCl (200 mL) was heated at reflux for 9 hours. Then, the mixture was cooled to room temperature, basified to pH 8 with 2 N NaOH, extracted with CH2C|2 (3X300 mL), dried over anydrous MgSO4, filtered, and concentrated. The residue was ed by silica gel chromatography, eluting with 92:7:1 to 6:3:1 MeOH/concentrated NH4OH, to afford the title compound (1.13 g, 66%). 1H NMR (300 MHZ, DMSO-ds): 8 8.08 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.68 (d, J = 2.3 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), .23 (m, 4H), .84 (m, 4H); APCl MS m/z 367 [M+H]+.

Example 13. Preparation of N-(1-(4-(5,7-Dimethoxy—4-oxo—3,4-dihydroquinazolin- 2-yl)phenyl)piperidinyl)acetamide A solution of ethyl robenzoate (16.5 g, 98.1 mmol) and piperidin—4-ol (10.0 g, 98.8 mmol) in DMSO (20 mL) was heated at 120 °C under nitrogen for 48 hours. The mixture was cooled to room temperature, poured into water (400 mL), and the solids were filtered off, washed with water, followed by hexane, to afford ethyl 4-(4-hydroxypiperidinyl)benzoate (20.0 g, 82%).

To a solution of ethyl 4-(4-hydroxypiperidin-1—yl)benzoate (8.0 g, 32.1 mmol) in CH2CI2 (200 mL) was added Et3N (23 mL, 165 mmol) under nitrogen, followed by MsCl (5.6 g, 48.9 mmol). The mixture was stirred for minutes, washed with water (300 mL), dried over anhydrous M9804, filtered, and concentrated to afford ethyl 4—(4—(methylsulfonyloxy)piperidinyl)benzoate as a tan solid (10.5 g, 100%).

To a solution of ethyl 4-(4-(methylsulfonyloxy)piperidinyl)benzoate (10.5 g, 32.1 mmol) in DMF (50 mL) was added sodium azide (4.17 g, 64.2 mmol).

The mixture was heated at 80 °C for 5 hours cooled to room temperature, diluted with brine (300 mL), and extracted with ethyl acetate (400 mL). The organic phase was washed with brine (2X300 mL), dried over anyhydrous MgSO4, filtered, and concentrated, to afford ethyl 4—(4-azidopiperidiny|)benzoate as a yellow solid (7.62 g, 87%).

To a solution of ethyl 4—(4-azidopiperidinyl)benzoate (7.62 g, 27.8 mmol) in dioxane (190 mL) was added acetic acid (27 mL) and water (54 mL).

Then, 10% Pd/C (0.750 g) was added and the mixture was hydrogenated under 1 atmosphere of hydrogen for 5 hours. The mixture was filtered through Celite, concentrated, and 0.5 M HCI (500 mL) was added. The solution was washed with ethyl acetate (2X300 mL) and the aqueous phase basified with ammonium hydroxide, to pH 12. The aqueous phase was saturated with sodium chloride, extracted with CH2C|2 (2X300 mL), dried over anhydrous M9804, filtered, and concentrated, to afford ethyl 4—(4-aminopiperidin—1-yl)benzoate.

To a on of ethyl 4-(4-aminopiperidinyl)benzoate (1.65 g, 6.65 mmol) in CHzClz (200 mL) was added Et3N (1.35 g, 13.3 mmol), ed by acetyl chloride (0.573 g, 7.3 mmol). The on mixture was stirred at room temperature for 5 minutes, washed with brine (300 mL), dried over ous NaZSO4, filtered, and concentrated, to afford ethyl 4—(4—acetamidopiperidin—1- yl)benzoate as a white solid (1.9 g, 100%).

A solution of ethyl 4—(4-acetamidopiperidin—1—yl)benzoate (0.123 g, 0.42 mmol) in CH2C|2 (10 mL) under nitrogen at -78°C was treated with DIBAL-H (1.0M in hexanes, 0.950 mL, 0.95 mmol) dropwise, via a syringe. After minutes, the mixture was warmed to room temperature, stirred for 1 hour, and quenched with 10% le’s salt. After stirring for 10 minutes, CHZCIZ (50 mL) was added, and the ng was continued for 15 additional minutes. The layers were separated and the aqueous phase was ted with CHgClz (50 mL) and ethyl acetate (50 mL). The combined organic phases were dried (MgSO4), filtered, concentrated, and ed by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate to afford N~(1—(4-(hydroxymethyl)phenyl)piperidin—4—yl)acetamide as a white solid (0.025 g, 24%).

A mixture of N-(1-(4-(hydroxymethyl)phenyl)piperidin-4—yl)acetamide (0.380 g, 1.53 mmol), TPAP (0.026 g, 0.08 mmol), NMO (0.268 g, 2.30 mmol), and molecular sieves (3 Angstrom, 0.300 g) in CHzClz was stirred at room temperature for 19 hours. The mixture was filtered through Celite, concentrated, and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% MeOH/ethyl e, to afford N-(1—(4—formylphenyl)piperidin yl)acetamide as a white solid (0.280 g, 74%).

A mixture of N—(1-(4-formylphenyl)piperidinyl)acetamide (0.280 g, 1.14 mmol), 2-amino—4,6-dimethoxybenzamide (0.224 g, 1.14 mmol), p-TsOH (0.022 g, 0.114 mmol), and NaHSOs (0.125 g, 1.21 mmol) in DMA was heated at 155 °C for 6 hours. The reaction e was cooled, d with water (100 mL), basified with saturated NaHC03, and extracted with ethyi e (3X150 mL). The organic phase was concentrated and purified by flash chromatography on silica gel, eiuting with 1:1 CHZC|2/(92:7:1 CHClg/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCIg/MeOH/concentrated NH4OH. Further purification by reverse—phase HPLC, eluting with 10% to 90% CchN in H20 with 0.1% TFA, ed the title compound as a yellow solid (0.140 g, 29%): 1H NMR (300 MHz, DMSO-de): 8 11.74 (s, 1H), 8.08 (d, J: 9.0 Hz, 2H), 7.83 (d, J: 7.7 Hz, 1H), 7.01 (d, J: 9.0 Hz, 2H), 6.68 (d, J = 2.3 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 37-389 (m, 9H), 2.92- 3.00 (m, 2H), 1.76-1.85 (m, 5H), 1.36-1.48 (m, 2H); APCI MS m/z 423 [M+H]+.

Example 14. Preparation of 4—(5,7-Dimethoxyoxo-3,4-dihydroquinazolin— 2-yl)phenyl)piperidin-4—yl)methanesulfonamide A mixture of 2-(4~(4—aminopiperidinyl)phenyl)-5,7— dimethoxyquinazo|in~4(3H)—one (0.105 g, 0.28 mmol), methanesulfonylchloride (0.035 g, 0.30 mmol), and Et3N (0.057 g. 0.56 mmol) in CH2C|2 (10 mL) was stirred at room temperature under nitrogen for 2 hours. The mixture was concentrated, redissolved in THF (5 mL), 2 M NaOH (5 mL) added and stirred for minutes. The pH was adjusted to 8 with 1 M HCl and the mixture extracted with CH2CI2 (3X150 mL). The organic phase was dried over anhydrous M9804, ed, and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 CH2C|2/(92:7:1 CHCI3/MeOH/ concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. Further purification by reverse-phase HPLC. eluting with 10% to 90% CH30N in H20 with 0.1% TFA. afforded the title compound as a yellow solid (0.075 g, 58%). 1H NMR (300 MHz, DMSO—de): 611.75 (s, 1H), 8.08 (d, J = 9.0 Hz, 2H), 7.13 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 2.3 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 3.81—3.94 (m, 8H), 3.34—3.47 (m, 1H), 2.90 (m, 6H), 1.87-1.95 (m, 2H), 1.42—1.54 (m, 2H); ESl MS m/z 459 [M+H]+.

Example 15. Preparation of 3-(1-(4-(5,7-Dimethoxy—4-oxo—3,4—dihydroquinazolin- 2-yl)phenyl)piperidinyl)-1,1-dimethylurea /o o A mixture of N—(1—(4—(5,7-dimethoxy-4—oxo—3,4-dihydroquinazolin—Z— yl)pheny|)piperidin-4—y|)acetamide (0.250 g, 0.59 mmol) and 2 M HCI (20 mL) was heated at reflux for 24 hours. The mixture was basified with 2 M NaOH to pH 8, ted with CH2CI2 (3X150 mL), dried over ous M9804, filtered, and trated to afford 2-(4-(4-aminopiperidinyl)phenyI)-5,7- dimethoxyquinazolin-4(3H)-one as a yellow solid (0.215 g, 96%).

A mixture of 2-(4—(4-aminopiperidiny|)pheny|)-5,7- dimethoxyquinazolin-4(3H)-one (0.105 g, 0.28 mmol), dimethylcarbamic chloride (0.032 g, 0.30 mmol), and Et3N (0.085 g, 0.84 mmoi) in THF (10 mL) was stirred at room temperature for 18 hours. The mixture was then heated at reflux for 24 hours, then cooled to room temperature. 2 M NaOH (20 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was adjusted to pH 8, extracted with CH2C|2 (3X100 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was dissolved in CHCI3/MeOH and concentrated, then CH3CN was added and concentrated to afford the title compound as a white solid (0.065 g, 51%): 1H NMR (300 MHz,CDCl3):611.72(s, 1H), 8.08 (d, J: 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 2.2 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), .99 (d, J = 7.8 Hz, 1H), 3.90-3.94 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.66-3.69 (m, 1H), 2.88—2.93 (m, 2H), 2.76 (s, 6H), 1.75-1.80 (m, 2H), .52 (m, 2H); ESI MS m/z 452 [M+H]+.

Example 16. Preparation of 2-(4-(4-Hexanoylpiperazinyl)phenyl)—5,7- dimethoxyquinazolin-4(3H)—one To a solution of 5,7-dimethoxy—2-(4-(piperazin—1- yl)phenyl)quinazolin-4(3H)~one (0.120 g, 0.32 mmol) in CHZCIZ (10 mL) was added Et3N (0.06 mL, 0.48 mmol) and hexanoyl chloride (0.03 mL, 0.28 mmol).

The resulting on was stirred at room temperature for 1 hour. The mixture was trated in vacuo. The material was purified by flash chromatography, eluting with 2% to 10% of MeOH/CHZCIZ, to afford the title compound (0.050 g, 38%). 1H NMR (300 MHz, DMSO-d6)2811.79(s, 1H), 8.11 (d, J: 8.7 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.75-4.05 (m, 6H), 3.47-3.73 (m, 4H), 3.17-3.43 (m, 4H), 2.20-2.40 (m, 2H), 1.41-1.62 (m, 2H), 1.15-1.38 (m, 4H), 0.76- 0.98 (m, 3H); APCl MS m/z 465 [M+H]+.

Example 17. Preparation of 2-(4-(4-Isobutyrylpiperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one /o o To a on of 5,7-dimethoxy-2—(4-(piperazin yl)phenyl)quinazolin—4(3H)—one (0.150 g, 0.40 mmol) in CH2CI2 (10 mL) was added Eth (0.08 mL, 0.60 mmol) and isobutyryl chloride (0.03 mL, 0.36 mmol).

The resulting solution was stirred at room temperature for 1 hour. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 2% to 10% of MeOH/CHZCIZ, The solid was further ed by flash tography on silica gel, eluting with 0% to 5% of MeOH/EtOAc, to afford the title compound (0.080 g, 50%): 1H NMR (300 MHz, DMSO-de):611.78(s, 1H), 8.11 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.1 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.76-3.92 (m, 6H), 3.52-3.71 (m, 4H), 3.16—3.44 (m, 4H), 2.83—3.00 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H); APCI MS m/z 437 [M+H]+.

Example 18. Preparation of 2-(4-(4—Benzoylpiperazinyl)pheny|)-5,7- dimethoxyquinazolin-4(3H)~one To a solution of 5,7-dimethoxy-Z—(4-(piperazin yl)phenyl)quinazolin—4(3H)—one (0.150 g, 0.40 mmol) in CH2C|2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and l chloride (0.04 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. The al was ed by flash chromatography on silica gel eluting with 0% to 10% of MeOH/EtOAc to afford the title compound (0.110 9,64%).1H NMR (300 MHz, DMSO-ds):611.79(s, 1H), 8.11 (d, J: 8.7 Hz, 2H), 7.37-7.54 (m, 5H), 7.04 (d, J = 8.9 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.61-4.03 (m, 8H), 3.23—3.62 (m, 6H); ESI MS m/z 471 [M+H]+.

Example 19. Preparation of 2-(4-(4—(4-Fluorobenzoyl)piperaziny|)phenyl)-5,7- dimethoxyquinazolin-4(3H)—one To a solution of 5,7-dimethoxy—2-(4—(piperazin—1- yl)phenyl)quinazolin-4(3H)—one (0.150 g, 0.40 mmol) in CH2C|2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and robenzoyl chloride (0.04 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 0% to 10% of tOAc, to afford the title compound (0.080 g, 45%). 1H NMR (300 MHz, DMSO-d5)I 6 11.79 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.44—7.62 (m, 2H), 7.21-7.39 (m, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.64—3.94 (m, 8H), 3.22—3.60 (m, 6H); APCI MS m/z 489 [M+H]+.

Example 20. Preparation of N-(1-(4-(5,7—Dimethoxy-4—oxo-3,4-dihydroquinazolin— 2—yl)phenyl)piperidin-4—yl)benzamide To a solution of ethyl 4-(4—aminopiperidin-1—yl)benzoate (3.0 g, 12.1 mmol) in CHzclz under nitrogen was added Et3N (2.45 g, 24.2 mmol), followed by benzoyl chloride (1.70 g, 12.1 mmol). The mixture was stirred at room temperature overnight, washed with brine (200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The resulting solids were triturated with hexanes to afford ethyl enzamidopiperidinyl)benzoate as a yellow solid (42 g, 100%).

A solution of ethyl 4—(4-benzamidopiperidiny|)benzoate (4.2 g, 11.9 mmol) in THF (400 mL) was cooled to 0°C under nitrogen and treated with DlBAL-H (1.0 M in THF, 47 mL, 47 mmol). The mixture was warmed to room temperature and stirred for 1 hour. Then, the reaction mixture was quenched with Rochelle’s salt (10% aqueous), concentrated to remove the THF, brine (300 mL) was added, and the organic phase was extracted with CH2C|2 (3X200 mL), dried over ous MgSO4, ed, and concentrated, to afford N-(1-(4— xymethyl)phenyl)piperidinyl)benzamide as a yellow solid that was used without further purification.

To a solution of N-(1-(4—(hydroxymethyl)phenyl)piperidin-4— yl)benzamide (1.1 g, 3.5 mmol) in CHzClz (250 mL) was added TPAP (0.123 g, 0.35 mmol) and NMO (0.623 g, 5.3 mmol). After 1 hour, the mixture was filtered through Celite, concentrated, and purified by silica gel chromatography, eluting with 30% ethyl acetate/hexanes to 100% ethyl acetate, to afford N-(1-(4- formylpheny|)piperidinyl)benzamide as a white solid (0.350 g, 32%).

A mixture of N—(1~(4-formylphenyl)piperidin—4-yl)benzamide (0.350 g, 1.10 mmol), NaHSO3 (0.180 g, 1.70 mmol) and p—TsOH (0.022 g, 0.11 mmol) and 2-amino—4,6-dimethoxybenzamide (0.223 g, 1.10 mmol) in DMA (10 mL) was heated at 150 °C overnight. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc and washed with H20 and brine, dried (Na2804), filtered and concentrated in vacuo. The resulting solid was purified by silica gel tography eluting with 10% to 50% CHCI3/MeOH/concentrated NH4OH in CH2C|2 to afford the title compound (0.050 g, 10%): 1H NMR (300 MHz, 6)2611.75(s, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.10 (d, J = 9.0 Hz, 2H), 7.83 (d, J = 6.9 Hz, 2H), 7.44-7.49 (m, 3H), 7.05 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.93-4.17 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.91-3.08 (m, 2H), 1.82-1.93 (m, 2H), 1.52-1.72 (m, 2H); APCI MS m/z 485 [M+H]+.

Example 21. Preparation of 5,7—Dimethoxy—2—(4-(4-picolinoylpiperazin y|)phenyl)quinazolin-4(3H)—one To a solution of picolinic acid (0.066 g, 0.54 mmol) in THF (20 mL) was added HOBt (0.079 g, 0.59 mmol), EDCI (0.113 g, 0.59 mmol), Et3N (0.08 mL, 0.59 mmol) and 5,7-dimethoxy—2—(4—(piperazinyl)pheny|)quinazolin—4(3H)— one (0.200 g, 0.54 mmol). The resulting solution was stirred overnight at room temperature. The solution was trated in vacuo and the resulting solid was purified by flash tography on silica gel, g with 50% to 100% of 92:7:1 CHCI3/MeOH/concentrated NH4OH in CH2CI2, to afford the title nd (0.160 g, 62%): 1H NMR (300 MHz, DMSO—d5)2611.69(s, 1H), 8.53-8.70 (m, 1H), 8.11 (d, J = 8.9 Hz, 2H), 7.86-8.04 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.44-7.57 (m, 1H), 7.04 (d, J = 9.1 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.74—3.97 (m, 8H), 3.53— 3.68 (m, 2H), 3.41—3.53 (m, 2H), 3.23—3.39 (m, 2H). APCI MS m/z 472 [M+H]+.

Example 22. Preparation of 5,7-Dimethoxy-2—(4—(4—nicotinoylpiperazin—1- yl)phenyl)quinazolin-4(3H)—one /o o To a solution of nicotinic acid (0.066 g, 0.54 mmol) in THF (20 mL) was added HOBt (0.079 g, 0.59 mmol), EDCI (0.113 g, 0.59 mmol), EtsN (0.08 mL, 0.59 mmol) and 5,7-dimethoxy—2—(4-(piperazin-1—yl)phenyl)quinazolin—4(3H)- one (0.200 g, 0.54 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting solid was purified by flash chromatography on silica gel, eluting with 10% to 60% of 922721 CHCl3/MeOH/concentrated NH4OH in CHZClz, to afford the title nd (0.050 g, 19%): 1H NMR (300 MHz, DMSO-ds): 6 11.79 (s, 1H), 8.59—8.78 (m, 2H), 8.12 (d, J = 8.8 Hz, 2H), .99 (m, 1H), 7.37-7.60 (m, 1H), 7.04 (d, J = 9.1 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.63-3.97 (m, 8H), 3.20-3.63 (m, 6H). APCI MS m/z 472 [M+H]+.

Example 23. Preparation of 4-lsonicotinoylpiperazinyl)phenyl)—5,7— dimethoxyquinazolin-4(3H)—one To a solution of isonicotinic acid (0.083 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCI (0.141 g, 0.74 mmol), Et3N (0.10 mL, 0.74 mmol) and 5,7-dimethoxy—2-(4—(piperazin-1—yl)phenyl)quinazolin- 4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was d overnight at room temperature. The solution was concentrated in vacuo and the resulting material was purified by flash chromatography on silica gel, eluting with 10% to 60% of 92:7:1 MeOH/concentrated NH4OH in CHZClz, to afford the title compound (0.110 g, 34%). 1H NMR (300 MHz, DMSO—ds): 5 11.79 (s, 1H), 8.58- 8.79 (m, 2H), 8.12 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 6.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.64-4.06 (m, 9H), 3.22—3.54 (m, 5H). APCI MS m/z 472 [M+H]+. e 24. Preparation of methoxy~2—(4-(4—(thiophene-2— carbonyl)piperazinyI)phenyl)quinazolin-4(3H)-one To a solution of 2—thiophenecarboxylic acid (0.087 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCI (0.141 g, 0.74 mmol), Eth (0.10 mL, 0.74 mmol) and 5,7-dimethoxy(4-(piperazin yl)phenyl)quinazolin-4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was stirred at room temperature for 4 hours. The on was concentrated in vacuo.

The material was purified by flash chromatography, eluting with 0% to 50% of 92:7:1 CHCl3/MeOH/ concentrated NH4OH in CHZCIZ, to afford the title compound (0.100 9,30%).1H NMR (300 MHz, DMSO—d5)2611.78(s, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.75-7.84 (m, 1H), 7.46-7.53 (m, 1H), 7.12-7.20 (m, 1H), 7.03 (d, J = 9.1 Hz, 2H), 6.69 (d, J = 2.3 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.74-3.92 (m, 4H), 3.37-3.49 (m, 4H). APCI MS m/z 477 [M+H]+.

Example 25. Preparation of 2-(4-(4-(5-Chloro—1—methyl-1H—pyrazole—4— carbonyl)piperazlnyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one To a mixture of 5,7-dimethoxy—2-(4-(piperazin—1— yl)phenyl)quinazolin-4(3H)—one (0.150 g, 0.41 mmol) and 5—chloromethyl-1H— pyrazolecarbonyl chloride (0.073 g, 0.41 mmol) in CH2C|2 (50 mL), was added Eth (0.086 mL, 0.62 mmol) and the reaction stirred under nitrogen at room temperature for 1 hour. The residue was trated and purified by flash chromatography on silica gel, g with 70% CHZCl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford the title compound as a white solid (0.159 g, 76%). 1H NMR (500 MHz, DMSO-de):611.78(s, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 7.04 (d, J: 9.1 Hz, 2H), 6.69 (d, J = 2.3 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.80-3.87 (m, 6H), 3.63-3.80 (m, 4H), 3.38—3.44 (m, 4H). APCI MS m/z 509 [M+H]+. e 26. Preparation of 5,7-Dimethoxy-2—(4-(4-(3,3,3— trifluoropropanoyl)piperazinyl)phenyl)quinazolin-4(3H)—one To a on of 5,7-dimethoxy(4-(piperazin—1— yl)phenyl)quinazolin—4(3H)—one (0.200 g, 0.54 mmol) in THF (10 mL) was added EDCl (0.105 g, 0.54 mmol), HOBt (0.074 g, 0.54 mmol), Et3N (0.08 mL, 0.54 mmol) and trifluoropropionic acid (0.070 g, 0.54 mmol). The reaction was stirred at room temperature for 4 hours and concentrated in vacuo. Purification by flash chromatography, eluting with 20% to 100% of 92:7:1 CHCI3/MeOH/concentrate NH4OH in CH2C|2, afforded the title compound (0.135 g, 52%). 1H NMR (300 MHz, DMSO-de): 5 11.78 (s, 1H), 8.10 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 2.3 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), .78 (m, 2H), 3.60-3.67 (m, 4H), 3.34-3.38 (m, 4H). APCI MS m/z 477 [M+H]+.

Example 27. Preparation of 2-(4~(4-(2,5-Dichlorothiophene—B—carbonyl)piperazin- 1-yl)phenyl)—5,7-dimethoxyquinazolin-4(3H)—one /o o To a mixture of 5,7-dimethoxy—2-(4—(piperazin yl)phenyl)quinazolin-4(3H)—one (0.150 g, 0.41 mmol) and 2,5-dichlorothiophene—3- carbonyl chloride (0.088 g, 0.41 mmol) in CH2C|2 was added Eth (0.086 mL, 0.62 mmol) and the mixture stirred at room temperature under nitrogen for 30 minutes.

The mixture was concentrated and ed by silica gel chromatography, eluting with 70% CH2C|2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 MeOH/concentrated NH4OH), to afford the title nd as a light yellow solid (0.177 g, 79%). 1H NMR (300 MHz, DMSO-ds):611.80(s, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J = 9.0 Hz, 2H), 6.69 (cl, J = 2.3 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.73-3.82 (m, 2H), 3.38-3.44 (m, 6H). APCI MS m/z 545 [M+H]+.

Example 28. Preparation of 2—(4—(4-(Cyclopropanecarbonyl)piperazin-1— yl)phenyl)—5,7-dimethoxyquinazolin-4(3H)-one /o o To a solution of 5,7—dimethoxy—2—(4-(piperazin—1— yl)phenyl)quinazolin-4(3H)—one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol), and cyclopropane carbonyl chloride (0.03 mL, 0.36 mmol). The ing solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the material was purified by flash chromatography on silica gel eluting with 0% to 50% of 92:7:1 CHCI3/MeOH/concentrated NH4OH in Cchlz to afford the title compound (0.100 9,63%).1H NMR (300 MHz, DMSO—ds):611.78(s, 1H), 8.12 (d, J: 8.9 Hz, 2H), 7.04 (d, J = 9.2 Hz, 2H), 6.63-6.74 (m, 1H), .52 (m, 1H), 3.73-3.95 (m, 8H), 3.51-3.73 (m, 2H), .49 (m, 4H), 1.93-2.10 (m, 1H), .83 (m, 4H). APCI MS m/z 435 [M+H]+.

Example 29. Preparation of 2-(4-(4-(4-F|uorobenzy|)piperazinyl)phenyl)-5,7- dimethoxyquinazolin—4(3H)-one .ngNH To a solution of 5,7-dimethoxy-2~(4-(piperazin-1— yl)phenyl)quinazolin—4(3H)-one (0.200 g, 0.55 mmol) in DMF (5 mL) was added 4- fluorobenzyl bromide (0.07 mL, 0.55 mmol) and K2C03 (0.15 g, 1.10 mmol). The reaction was stirred at room temperature for 2 hours then diluted with H20 and the solids filtered off to afford the title compound (0.17 g, 65%) as a light brown solid. 1H NMR (300 MHz, DMSO-ds):611.76(br s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.26- 7.52 (m, 2H), 7.08-7.25 (m, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 2H), 3.08-3.41 (m, 4H), 2.23—2.68 (m, 4H).

APCI MS m/z 475 [M+H]+.

Example 30. Preparation of 4-Benzylpiperazin—1-yl)phenyl)—5,7— dimethoxyquinazolin-4(3H)-one Following the method described for Example 29 above, the title compound was made from benzyl bromide in 45% yield. 1H NMR (300 MHz, DMSO-ds): 6 11.76 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.26-7.43 (m, 5H), 7.00 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.53 (s, 2H), 3.23-3.40 (m, 4H), 2.38-2.63 (m, 4H). APCl MS m/z 457 [M+H]+.

Example 31. Preparation of 2-(4-(4-(2,2,2-Trifluoroethyl)piperazin-1— yl)phenyl)quinazolin-4(3H)—one Ndwas: (:[H/NH To a mixture of 2—aminobenzamide (1.0 g, 7.35 mmol) and 4—(4- acetylpiperazinyl)benzaldehyde (1.71 g, 7.35 mmol) in DMA (60 mL) was added p—TsOH (0.140 g, 0.73 mmol) and NaH803 (0.841 g, 8.1 mmol). The reaction mixture was heated at 150 °C for 21 hours, concentrated to half-volume, diluted with water (300 mL), extracted with CH2CI2 (2X200 mL), washed with brine (200 mL), dried over anhydrous MgSO4, filtered, and trated. The residue was purified by silica gel chromatography, eluting with 100% CHZCIZ to 100% (922721 CHCI3/MeOH/ concentrated NH4OH), to afford 2-(4-(4—acetylpiperazin yl)phenyl)quinazolin-4(3I-I)-one as a yellow solid (2.27 g, 89%).

A mixture of 2-(4-(4—acetylpiperazin—1-yl)phenyl)quinazolin-4(3H)- one (2.27 g, 6.5 mmol) and 2 N HCI (100 mL) were heated at 100 °C for 4 hours.

Then, the mixture was cooled to room ature, basified to pH 8 with 2 N NaOH, extracted with CH2C|2 (3X150 mL), dried over ous MgSO4, filtered, and concentrated to afford 2-(4-(piperazin~1-yl)phenyl)quinazolin-4(3H)-one as a pale yellow solid (1.8 g, 90%).

To a mixture of 2-(4-(piperazinyl)phenyl)quinazolin-4(3H)—one (0.325 g, 1.06 mmol) in THF (50 mL) was added ig’s base (0.192 g, 1.48 mmol), followed by 2,2,2—trifluoroethyl trifluoromethanesuIfonate (0.295 g, 1.3 mmol). The reaction mixture was heated at reflux for 15 hours, concentrated, and purified by flash chromatography on silica gel, eluting with 100% CH2Cl2 to 100% ethyl acetate, to afford the title compound as an off—white solid (0.385 g, 94%). 1H NMR (300 MHz, DMSO-d5):812.27(br s, 1H), 8.10—8.14 (m, 3H), 7.76- 7.82 (m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.42—7.47 (m, 1H), 7.05 (d, J = 9.1 Hz, 2H), 3.21-3.34 (m, 6H), 2.73-2.78 (m, 4H). APCI MS m/z 389 [M+H]+.

Example 32. Preparation of 2—(4-(4-AcetyI-1,4-diazepany|)phenyl)—5,7- dimethoxyquinazolin-4(3H)—one {0218]A mixture of 4—fluorobenzaldehyde (1.56 g, 12.6 mmol), 1-(1,4— diazepanyl)ethanone (1.5 g, 10.5 mmol), and K2003 (1.74 g, 12.6 mmol) in DMF (10 mL) were heated at 120 °C for 20 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl e and the organic phase washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/hexanes to 100% ethyl acetate to 10% methanol/ethyl acetate, to afford 4-(4-acetyI—1,4—diazepanyl)benzaldehyde (1.8 g, 70%).

To a mixture of 2-aminc-4,6-dimethoxybenzamide (0.377 g, 1.92 mmol) and 4-(4-acetyl—1,4—diazepan-1—yl)benzaldehyde (0.520 g, 2.11 mmol) in DMA (20 mL) was added NaH803 (0.240 g, 2.3 mmol) followed by p-TsOH (0.037 g, 0.192 mmol) and the on heated at 150 °C for 6 hours. The mixture was cooled to room temperature, diluted with CHzclz (150 mL), washed with brine (2X150 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was ed by flash chromatography on silica gel, g with 1:1 CHgCl2/92z7z1 CHCI3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCI3/MeOH/concentrated NH4OH, to afford the title compound (0.333 g, 41%) as a yellow solid. 1H NMR (300 MHz, CDCI3): 8 9.12 (s, 1H), 7.88—7.91 (m, 2H), .82 (m, 3H), 6.42 (d, J: 2.2 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.62-3.80 (m, 6H), .48 (m, 2H), 1.98-2.12 (m, 5H). ESl MS m/z 421 [M-H]'.

Example 33. Preparation of 2-(4-(1 ,4—Diazepanyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one /O O A mixture of 2-(4-(4-acetyI—1,4-diazepanyl)phenyl)—5,7- dimethoxyquinazolin-4(3H)—one (0.135 g, 0.32 mmol) and 2 N HCI (10 mL) was heated at 100 °C for 4 hours. Then, the reaction mixture was cooled to room ature, basified to pH 8, and extracted with CH2C|2 (8X125 mL). The residue was purified by flash chromatography on silica gel, eluting with 1:1 CHgCl2/92z7z1 CHCI3/MeOH/concentrated NH4OH’to 100% 92:7:1 CHCI3/MeOH/concentrated NH4OH, to afford the title compound (0.040 g, 33%) as a yellow solid. 1H NMR (300 MHz, : 8 8.98 (s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 6.76-6.79 (m, 3H), 6.40 (d, J = 2.3 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.61—3.69 (m, 5H), 3.05 (t, J = 4.9 Hz, 2H), 2.83 (t, J = 5.7 Hz, 2H), 1.92 (t, J = 5.4 Hz, 2H). ESl MS m/z 379 .

Example 34. Preparation of 5,7—Dimethoxy—2-(4-(4-methyl-1,4—diazepan-1— yl)phenyl)quinazolin—4(3H)—one To a solution of 2—(4-(1,4—diazepan-1—yl)phenyl)—5,7- dimethoxyquinazolin—4(3H)—one (0.150 g, 0.39 mmol) in DMF (20 mL) was added CH3I (0.067 g, 0.47 mmol) and HUnig’s Base (0.138 mL, 0.79 mmol). The reaction mixture was heated at 50 °C for 1.5 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine (2X100 mL), dried over anhydrous MgSO4, filtered, and trated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2CI2/92z7z1 Me0H/concentrated NH40H to 100% 92:7:1 CHCI3/ MeOH/concentrated NH40H, to afford the title nd (0.035 g, 23%) as a white solid. 1H NMR (300 MHz, DMSO-de):811.66(s, 1H), 8.06 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.65 (d, J = 2.2 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.57-3.59 (m, 2H), 3.52 (t, J = 6.1 Hz, 2H), 2.60-2.64 (m, 2H), 2.45-2.50 (m, 2H), 2.26 (s, 3H), 1.89-1.99 (m, 2H). ESI MS m/z 395 [M+H]+.

Example 35. Preparation of N-(1-(4-(5,7—Dimethoxy-4—oxo-3,4—dihydroquinazolin— 2-yl)phenyl)piperidinyl)-N—ethylacetamide To a solution of 4-acetamidopiperidine (2.5 g, 17.5 mmol) in DMF (10 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol) and K2003 (2.9 g, 21.2 mmol). The reaction was heated at 120 °C for 4 hours, d with H20, and extracted with EtOAc. The organics were washed tially with H20 and brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford N—(1-(4- formylphenyl)piperidin—4—yl)acetamide (3.1 g, 92%).

A 60% suspension in oil of NaH (0.113 g, 2.8 mmol) was added to a 0 °C on of N-(1-(4-formylphenyl)piperidin-4—yl)acetamide (0.700 g, 2.8 mmol) in DMF (10 mL) and stirred for 35 minutes. To this mixture was added Etl (0.23 mL, 2.8 mmol) and the reaction was warmed to room temperature for 2 hours, quenched with H20, and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2804, filtered, and concentrated in vacuo.

Purification by flash chromatography on silica gel, eluting with 0% to 5% MeOH/CH2CI2, afforded N—ethyl-N-(1-(4—formylphenyl)piperidin-4—yl)acetamide (0.490 g, 64%).

A mixture of N—ethyl-N-(1-(4-formylphenyl)piperidinyl)acetamide (0.385 g, 1.40 mmol), NaH803 (0.162 g, 1.50 mmol), and p-TsOH (0.024 g, 0.12 mmol) were added to a solution of 2—amino-4,6—dimethoxybenzamide (0.250 g, 1.20 mmol) in DMA (10 mL). The reaction was stirred at 150 °C for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H20 and extracted with EtOAc. The cs were washed with brine, dried over anhydrous NaZSO4, filtered, and trated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.300 g, 55%) as a yellow solid. 1H NMR (300 MHz, DMSO—ds): mixture of rotamers 611.76(s, 1H), 8.08 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 4.29-4.33 (m, 0.5H), 3.99-4.03 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.12—3.25 (m, 2H), 2.81-2.93 (m, 2H), 2.07 (s, 1.5H), 2.01 (s, 1.5H), 1.59-1.74 (m, 4.5H), 1.10 (t, J = 6.7 Hz, 1.5H), 0.99 (t, J = 6.7 Hz, 1.5H). ESl MS m/z 451 [M+H]+.

Example 36. Preparation of 2-(4-((3R,5S)Acetyl—3,5~dimethylpiperazin-1~ yl)phenyl)~5,7-dimethoxyquinazolin—4(3H)-one A mixture of 4—fluorobenzaldehyde (2.0 g, 16.1 mmol), 2,6- dimethylpiperazine (2.2 g, 19.3 mmol), and K2CO3 (2.7 g, 19.3 mmol) in DMF (10 mL) was heated at 120 °C for 4 hours. Then, the reaction was diluted with H20 and ted with EtOAc. The cs were washed with brine, dried (NaZSO4), ed and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 3% to 10% MeOH/CHzClz afforded 4—(3,5-dimethylpiperazin yl)benzaldehyde (2.0 g, 57%).

A solution of 4—(3,5-dimethylpiperazinyl)benzaldehyde (1.0 g, 4.6 mmoL) in CH2Cl2 (15 mL) was cooled to 0 °C and treated with Et3N (0.64 mL, 4.6 mmol) followed by acetyl chloride (0.33 mL, 4.6 mmol). The reaction stirred for 30 minutes, then trated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 50% EtOAc/CHZCIZ, afforded 4~(4-acetyl—3,5- dimethylpiperazinyl)benzaldehyde (1.0 g, 83%).

A mixture of 4—(4-acetyl-3,5—dimethylpiperazin-1—yl)benzaldehyde (0.580 g, 2.20 mmol), NaH803 (0.260 g, 2.40 mmol), and p—TsOH (0.039 g, 0.20 mmol) was added to a solution of 2—amino-4,6—dimethoxybenzamide (0.400 g, 2.20 mmol) in DMA (15 mL). The reaction was stirred at 120 °C for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H20 and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2804, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, g with 2% to 10% MBOH/CHzclg, afforded the title compound (0.400 g, 46%) as a yellow solid. 1H NMR (300 MHz, DMSO—ds): 6 11.78 (br s, 1H), 8.10 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 2.3 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), .64 (m, 2H), 3.71-3.95 (m, 8H), 2.87-3.07 (m, 2H), 2.06 (s, 3H), 1.25 (d, J = 6.2 Hz, 6H). ESI MS m/z 437 .

Example 37. Preparation of 2-(4—((3R,58)-3,5—Dimethylpiperazin—1-y|)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one A solution of 2—(4—(4-acetyl—3,5-dimethylpiperazin—1-yl)phenyl)-5,7- dimethoxyquinazolin-4(3H)—one (0.150 g, 0.34 mmol) in 2N HCl was heated at reflux temperature for 3 days. The reaction was cooled to room temperature, basified with 1N NaOH, and extracted with CHzciz. Purification by flash chromatography on silica gel, eluting with 0% to 15% MeOH/CH2CIZ, followed by r purification, eluting with 30% to 100% of 92:7:1 CHCI3/MeOH/concentrated NH4OH, ed the title compound (0.040 g, 30%) as a white solid. 1H NMR (300 MHz, DMSO—de): 6 11.98 (br s, 1H), 8.08 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 2.3 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.73-3.76 (m, 2H), .81 (m, 2H), 2.19-2.26 (m, 2H), 1.03 (d, J = 6.2 Hz, 6H). ESI MS m/z 395 [M+H]+.

Example 38. Preparation of 2-(4-(4-AcetyI-3—methylpiperazinyl)phenyl)~5,7- dimethoxyquinazolin—4(3H)—one To a solution of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol) in DMF (10 mL) was added 2-methylpiperazine (1.9 g, 19.3 mmol) and K2C03 (2.7 g, 19.3 mmol). The reaction was heated at 120 °C for 6 hours, d with H20, and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2804, filtered, and concentrated in vacuo, to afford 4-(3-methylpiperazin yl)benzaldehyde (2.3 g, 69%): 1H NMR (300 MHz, CDCI3): 6 9.77 (s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 3.67-3.83 (m, 2H), 3.07-3.18 (m, 1H), 2.81-3.06 (m, 3H), 2.50262 (m, 1H), 1.46—1.73 (br s, 1H), 1.15 (d, J: 6.3 Hz, 3H). ESI MS m/z 205 [M+H]+.

A solution of 4-(3-methylpiperazinyl)benzaldehyde (1.0 g, 4.89 mmol) in methylene chloride (15 mL) was cooled to 0 °C and treated with Et3N (0.68 mL, 4.89 mmol), followed by acetyl chloride (0.34 mL, 4.89 mmol). The resulting solution was d at 0 °C for 20 minutes and then concentrated in vacuo. The material was ed by flash chromatography on silica gel, g with 0% to 5% of EtOAc/Cchlz, to afford 4-(4-acetylmethylpiperazin yl)benzaldehyde (0.88 g, 73%).

To a solution of cetyl—3-methylpiperazin—1-yl)benzaldehyde (0.400 g, 1.62 mmol) in DMA (15 mL) was added 2-amino-4,6- dimethoxybenzamide (0.349 g, 1.78 mmol), NaH803 (0.201 g, 1.94 mmol) and p- TsOH (0.030 g, 0.16 mmol). The resulting solution was heated to 155 °C for 5 hours. The mixture was cooled to room temperature, diluted with water, extracted with CH2Cl2, washed with brine, dried (Na2804), filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCI3/MeOH/concentrated NH4OH in CH2C|2, to afford the title compound (0.150 g, 21%). 1H NMR (300 MHz, DMSO-de): mixture of rotamers 5 11.57 (S, 1H), 8.10 (d, J = 8.9 HZ, 2H), 6.90-7.14 (m, 2H), 6.68 (S, 1H), 6.46 (s, 1H), 4.42—4.75 (m, 0.5H), 4.03—4.42 (m, 1H), 3.61-4.02 (m, 8H), 3.41— 3.60 (m, 1H), 2.85-3.13 (m, 2H), 2.63—2.85 (m, 0.5H), 1.88-2.13 (m, 3H), .31 (m, 3H). ESI MS m/z 423 [M+H]+. e 39. Preparation of N-(1-(4-(5,7-Dimethoxy—4-oxo-3,4-dihydroquinazolin~ 2-yl)phenyl)pyrrolidin-3—yl)acetamide A on of 2-(4-(3-aminopyrrolidinyl)phenyl)-5,7— dimethoxyquinazolin-4(3H)—one (0.150 g, 0.41 mmol) in CH2C|2 (10 mL) was treated with Et3N (0.114 mL, 0.82 mmol), cooled to 0 0C, and acetyl chloride (0.029 mL, 0.41 mmol) was added. The mixture was stirred for 2 hours at room temperature, concentrated, and purified by flash chromatography on silica gel, eluting with 1:1 CH2C|2I9227z1 CHClg/MeOH/concentrated NH4OH to 100% 921721 MeOH/concentrated NH4OH. The mixture was further purified by flash chromatography on silica gel, eluting with 9:1 methylene chloride/methanol, to afford the title compound (0.130 g, 78%) as a yellow solid. 1H NMR (300 MHz, DMSO—da):811.67(s, 1H), 8.18 (d, J: 6.8 Hz, 1H), 8.14 (d, J = 6.8 Hz, 2H), 6.66 (d, J = 2.3 Hz, 1H), 6.60 (d, J = 9.0 Hz, 2H), 6.44 (d, J = 2.3 Hz, 1H), 4.36—4.39 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.13-3.59 (m, 5H), 2.15-2.22 (m, 1H), 1.90- 1.94 (m, 1H), 1.82 (s, 3H). ESI MS m/z 409 [M+H]+.

Example 40. Preparation of 2-(4-(4-lsopropylpiperazin—1—y|)pheny|)—8— methoxyquinazolin~4(3H)—one To a solution of omethoxy benzoic acid (2.0 g, 11.90 mmol) in THF (30 mL) was added EDCl (2.7 g, 14.3 mmol), HOBt (1.9 g, 14.3 mmol) and NMM (1.6 mL, 14.3 mmol). The reaction was stirred at room ature for 2 hours and then NH4OH (1 mL) in H20 (1 mL) was added. After stirring overnight, the reaction was diluted with H20 and extracted with CH2Cl2.

The organics were washed with brine, dried over anhydrous Na2804, filtered, and concentrated in vacuo. The solids were ded in EtZO and filtered off to afford 2—aminomethoxybenzamide (1.1 g, 56%). 1H NMR (300 MHz, DMSO—ds) 6 7.71 (br s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.08 (br s, 1H), 6.87 (d, J= 7.1 Hz, 1H), 6.45-6.53 (m, 1H), 6.26 (br s, 2H), 3.78 (s, 3H).

A e of 4-(4-isopropylpiperazin—1-yl)benzaldehyde (0.562 g, 2.40 mmol), NaH803 (0.310 g, 2.90 mmol), and p-TsOH (0.046 g, 0.24 mmol) was added to a solution of 2-amino-3—methoxybenzamide (0.400 g, 2.40 mmol) in DMA (15 mL). The reaction was stirred at 120 °C overnight. The mixture was diluted with H20 and saturated NaHC03 and extracted with CHZCIZ. The organics were washed with brine, dried (NaZSO4), filtered and concentrated in vacuo. cation by flash chromatography on silica gel eluting with 0% to 10% MeOH/CHZCIZ afforded the title compound (0.140 g, 15%). 1H NMR (300 MHz, DMSO-d5)2512.27(s, 1H), 8.10 (d, J = 8.9 Hz, 2H), .70 (m, 1H), 7.31—7.39 (m, 2H), 7.03 (d, J = 9.1 Hz, 2H), 3.93 (s, 3H), 3.27—3.32 (m, 4H), 2.64-2.75 (m, 1H), 2.56-2.59 (m, 4H), 1.00 (d, J = 6.6 Hz, 6H). ESI MS m/z 379 [M+H]+.

Example 41. Preparation of N-(1—(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolin— 2-y|)phenyl)piperidin-4—yl)-N-isopropylacetamide To the solution of tert—butyl 4-oxopiperidinecarboxylate (5.0 g, .09 mmol) in methanol (35 mL) was added isopropylamine (1.07 mL, 12.54 mmol), acetic acid (0.94 mL, 16.30 mmol) and sodium cyanoborohydride (1.0 g, 16.30 mmol). The resulting solution was stirred at room temperature for 1 hour, then quenched with water. The solution was concentrated in vacuo and olved in ethyl ether. The organics were extracted with 0.1 N HCl. The aqueous extracts were basified with 1 N NaOH (pH > 8) and extracted with ethyl ether. The organic ts were dried over anhydrous NaZSO4, filtered, and trated in vacuo, to afford utyl 4-(isopropylamino)piperidine-1— carboxylate (1.2 g, 41%) as a clear liquid.

To a 0 °C solution of tert—butyl 4-(isopropylamino)piperidine carboxylate (1.2 g, 5.19 mmol) in CH2Cl2 (18 mL) was added Et3N (1.44 mL, 10.38 mmol) followed by acetyl chloride (0.55 mL, 7.78 mmol). The resulting solution was stirred for 2.5 hours, then concentrated in vacuo. The material was purified by flash chromatography on silica gel, g with 0% to 5% of EtOAc/CHgClz, to afford utyl sopropylacetamido)piperidinecarboxylate (0.88 g, 59%).

A on of tert—butyl 4-(N-isopropylacetamido)piperidine—1- carboxylate (0.880 g, 3.09 mmol) in hydrogen chloride (4.0 M solution in 1,4- dioxane, 10 mL) was stirred at room temperature overnight. The resulting solution was concentrated in vacuo, basified with aqueous saturated NaHC03, and extracted with EtOAc. The cs were dried (NaZSO4), filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2C|2_ The residue was further purified by flash chromatography on silica gel, eluting with 100% of 92:7:1 CHCI3/MeOH/concentrated NH4OH, to afford N— pyl-N-(piperidinyl)acetamide hydrogen chloride (0.260 g, 45%) as a clear liquid.

To a solution of N-isopropyl—N~(piperidin-4—yl)acetamide hydrogen chloride (0.260 g, 1.41 mmol) in DMF (5 mL) was added 4—fluorobenzaldehyde (0.18 mL, 1.69 mmol) and K2CO3 (0.233 g, 1.69 mmol). The resulting solution was heated to 120 °C overnight, and cooled. The cooled solution was diluted with water and extracted with CHZCIZ. The organics were washed with brine, dried over anhydrous Na2804, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% MeOH/CHZCIZ, to afford N-(1-(4-formylphenyl)piperidinyl)—N-isopropylacetamide (0.290 g, 71%).

To a solution of N-(1-(4-formy|phenyl)piperidiny|)-N— isopropylacetamide (0.300 g, 1.04 mmol) in DMA (10 mL) was added 2-amino— 4,6-dimethoxybenzamide (0.204 g, 1.04 mmol), NaH803 (0.129 g, 1.24 mmol) and p—TsOH (0.019 g, 0.10 mmol). The resulting solution was heated to 155 °C overnight and then cooled to room temperature. The solution was diluted with water, extracted with CHZCI2, washed with brine, dried over anhydrous NaZSO4, ed, and concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting, with 30% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.100 g, 20%). 1H NMR (300 MHz, DMSO-ds): mixture of rotamers 5 11.66 (s, 1H), 8.07 (d, J = 8.3 Hz, 2H), 6.89-7.15 (m, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.90—4.11 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.80-3.02 (m, 2H), .66 (m, 1H), 1.92-2.06 (m, 3H), 1.63-1.82 (m, 2H), 1.32—1.47 (m, 1H), 1.21—1.32 (m, 3H), 1.08-1.21 (m, 4H). ESl MS m/z 463 [M-H]'.

Example 42. Preparation of ro(4-(4-isopropylpiperazin yl)phenyl)quinazolin-4(3H)-one A solution of 2-aminochlorobenzamide (0.314 g, 1.85 mmol) and 4-(4-isopropylpiperaziny|)benza|dehyde (0.430 g, 1.85 mmol) in DMA (25 mL) were treated with p-TsOH (0.035 g, 0.185 mmol) and NaH803 (0.212 g, 2.04 mmol), and the e was heated at 140 °C for 18 hours . Then, the mixture was cooled, diluted with CH2C|2 (200 mL), and washed with saturated NaH003 (100 mL). The organic phase was dried over anhydrous M9804, filtered, concentrated, and purified by silica gel chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCI3/MeOH/ concentrated NH4OH to 100% 92:7:1 CHCI3/MeOH/concentrated NH4OH to 100% 623:1 MeOH/concentrated NH4OH. The resulting solids were rechromatographed with 9:1 CH2Cl2/MeOH to afford the title compound as a white solid. 1H NMR (300 MHz, DMSO—de):812.24(br s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.66-7.71 (m, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 3.28-3.34 (m, 4H), 2.64-2.73 (m, 1H), 2.55—2.59 (m, 4H), 1.01 (d, J = 6.4 Hz, 6H). ESI MS m/z 383 [M+H]+.

Example 43. Preparation of 2-(4-((3R,5S)—4-lsopropyI-3,5—dimethylpiperazin yl)phenyl)~5,7-dimethoxyquinazolin—4(3H)—one To a e of 4-(3,5-dimethylpiperazinyl)benza|dehyde (1.0 g, 4.6 mmol) and K2003 (1.3 g, 9.2 mmol) in CH3CN (10 mL) was added 2- iodopropane (2.3 mL, 22.9 mmol) and the reaction was stirred at reflux ature overnight. Additional 2—iodopropane (2.3 mL, 22.9 mmol) and K2C03 (1.3 g, 9.2 mmol) were added and the reaction was continued to reflux overnight.

The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CHzClg, to afford 4-(4-isopropyl~3,5— dimethylpiperaziny|)benza|dehyde (0.550 g, 46%).

A mixture of 4-(4—isopropyl~3,5-dimethylpiperazin-1—y|)benza|dehyde (0.400 g, 1.50 mmol), NaH803 (0.195 g, 1.80 mmol), and p-TsOH (0.030 g, 0.15 mmol) was added to a solution of 2-amino—4,6~dimethoxybenzamide (0.400 g, 2.40 mmol) in DMA (10 mL). The reaction was stirred at 140 °C for 4 hours, then at room temperature overnight. The mixture was diluted with H20 and extracted with . The organics were washed with brine, dried (N32804), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% HgClz, followed by reverse-phase chromatography, g with 10% to 90% CH3CN in H20, afforded the title compound (0.114 g, 17%).1H NMR (300 MHz, s):611.68(s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.66 (s, 1H), 6.44 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.41- 3.44 (m, 2H), 3.11—3.23 (m, 5H), 1.00-1.03 (m, 12H). ESI MS m/z 437 [M+H]+.

Example 44. Preparation of 5,7—Dimethoxy-2—(4-(piperidin—4—yl)phenyl)quinazolin- 4(3H)—one /0mN\ /0 O To a solution of tert—butyl 4—(4~(5,7—dimethoxyoxo-3,4— dihydroquinazolinyl)phenyl)piperidine-1—carboxylate (0.210 g, 0.45 mmol) in 1,4-dioxane (2 mL) was added 4M HCI in 1,4~dioxane (1 mL). The resulting solution was d at room temperature for 5 hours. Then, the mixture was concentrated in vacuo and and the resulting material was purified by flash chromatography on silica gel, g with 0% to 10% of MeOH/CHzClg. The residue was r purified by flash chromatography on silica gel, eluting with 100% of 92:7:1 CHClg/MeOH Iconcentrated NH4OH followed by 100% of 6:3:1 CHCI3/MeOH/concentrated NH4OH, to afford the title compound (0.030 g, 18%). 1H NMR (300 MHz, DMSO—de): 5 8.11 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.92-3.20 (m, 2H), 2.56—2.81 (m, 3H), 2.35—2.57 (m, 2H), 1.67—1.88 (m, 2H), 1.38-1.67 (m, 2H). ESI MS m/z 366 Example 45. Preparation of 5,7-Dimethoxy(4-(3—(methylamino)pyrrolidin y|)phenyl)quinazolin-4(3H)-one /0 NYQ/ /0 o A mixture of N-(1-(4-(5,7-dimethoxy—4-oxo-3,4-dihydroquinazolin y|)phenyl)pyrrolidinyI)-N—methylacetamide (0.500 g, 1.18 mmol) and 2 N HCI (80 mL) was heated at 100 °C for 4 hours, cooled, basified to pH 9, extracted with CHZClz (2XZ00 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92z7z1 CHCI3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 6:321 CHCl3/MeOH/concentrated NH4OH, to afford the title nd (0.210 g, 47%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-ds): 8 11.65 (br s, 1H), 8.08 (d, J = 8.7 Hz, 2H), 8.85 (s 1H), 8.55 (d, J = 7.8 Hz, 2H), 8.43 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.46-3.49 (m, 1H), .42 (m, 1H), 3.26-3.28 (m, 2H), 3.07—3.10 (m, 1H), 2.31 (s, 3H), 2.08-2.11 (m, 1H), 1.81—1.84 (m, 1H). ESl MS m/z 381 [M+H]+.

Example 46. Preparation of Tert—butyl 4-(4—(5,7-dimethoxy—4-oxo—3,4— dihydroquinazolin—2-yl)phenyl)piperidine~1-carboxylate /o N\ /0 o A solution of 2-(4—bromophenyl)—5,7-dimethoxyquinazolin-4(3H)-one (1.1 g, 3.23 mmol), K2C03 (1.3 g, 9.69 mmol), PdCl2(dppf) (0.261 g, 0.32 mmol) and tert—butyl 4—(4,4,5,5-tetramethyl—1,3,2—dioxaborolan—2-yl)~5,6—dihydropyridine~ 1(2H)—carboxylate (1.0 g, 3.23 mmol) in DMF (50 mL) was heated to 110 °C overnight. The resulting solution was concentrated in vacuo and the material was purified twice by flash chromatography on silica gel, eluting with 0% to 5% of MeOH/CHZCIZ. The residue was further ed by flash chromatography on silica gel, eluting with 10% to 50% of EtOAc/CHZClg, to afford tert—butyl 4-(4-(5,7- dimethoxy—4-oxo—3,4-dihydroquinazolin-Z-yl)phenyl)—5,6-dihydropyrid ine-1 (2H)- carboxylate (0.030 g, 49%) as a light yellow solid.

A solution of ted-butyl 4-(4—(5,7-dimethoxy—4-oxo-3,4- oquinazolinyl)phenyl)-5,6—dihydropyridine-1(2H)—carboxy|ate (0.160 g, 0.34 mmol) in EtOH (10 mL) and HOAc (5 mL) was purged with nitrogen, and % Pd/C (0.016 g) was added. The mixture was stirred under 1 here of hydrogen ght. Then, the solution was filtered through Celite, with MeOH washings, and the filtrate was concentrated in vacuo. The al was purified by flash chromatography on silica gel, eluting with 30% to 70% of 92:7:1 CHCl3/MeOH/ concentrated NH4OH in CH2C|2, to afford the title compound (0.160 g, 100%).1H NMR (300 MHz, DMSO-d5)2611.91 (s, 1H), 8.11 (d, J: 8.3 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 4.00-4.22 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.65~2.97 (m, 3H), 1.68—1.88 (m, 2H), 1.48—1.68 (m, 2H), 1.42 (s, 9H). ESI MS m/z 466 [M+H]+.

Example 47. Preparation of 4-(5,7-dimethoxy—4-oxo—3,4-dihydroquinazolin- 2-yl)phenyl)pyrrolidin—3-yl)—N-methylacetamide A solution of 4-fluorobenzaldehyde (2.01 g, 16.2 mmol) and N— —N—(pyrrolidin—3—yl)acetamide (1.92 g, 13.5 mmol) in DMF (20 mL) was treated with K2C03 (2.24 g, 16.2 mmol). The mixture was heated at 120 °C under nitrogen for 18 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine, dried (Na2804), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% methanol/ethyl acetate, to afford N-(1-(4-formylphenyl)pyrrolidinyl)-N- methylacetamide.

A solution of 2~amino—4,6~dimethoxybenzamide (0.797 g, 4.07 mmol) and N-(1—(4—formylphenyl)pyrrolidin—3—yl)—N-methylacetamide (1.0 g, 4.07 mmol) in DMA (75 mL) was treated with NaH803 (0.466 g, 4.5 mmol) and p—TsOH (0.078 g, 0.41 mmol). The mixture was heated at 150 °C for 15 hours, cooled to room temperature, d with CH2C|2 (200 mL), and washed with saturated NaHC03 (100 mL) and water (200 mL). The c phase was dried over anhydrous M9804, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2CI2/9227z1 CHClg/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (1.5 g, 88%) as a light brown solid. 1H NMR (300 MHz, DMSO—ds): 8 11.68 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 6.55—6.67 (m, 3H), 6.44 (d, J = 2.2 Hz, 1H), 4.67-5.22 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), .60 (m, 2H), 3.22-3.26 (m, 2H), 2.76-2.89 (m, 3H), 1.91-2.27 (m, 5H). ESI MS m/z 423 [M+H]+.

Example 48. Preparation of 4-(lsopropylamino)piperidinyl)phenyl)—5,7~ dimethoxyquinazolin-4(3H)—one /o o A solution of N—(1—(4—(5,7-dimethoxyoxo—3,4—dihydroquinazolin-2— yl)phenyl)piperidinyl)-N—isopropylacetamide (0.130 g, 0.27 mmol) in 2 N HCl (8 mL) was heated to reflux and stirred overnight. The resulting solution was cooled to room temperature, basified with 2 N NaOH (pH 14), and extracted with CHzclz.

The solution was concentrated in vacuo and the e was purified by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CHgClg, to afford the title compound (0.060 g, 52%). 1H NMR (300 MHz, DMSO-de): 5 8.07 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.1 Hz, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.75—3.95 (m, 8H), 2.81—2.99 (m, 3H), 2.69- 2.79 (m, 1H), 1.79-1.92 (m, 2H), 1.14—1.37 (m, 3H), 0.97 (d, J: 6.1 Hz, 6H). ESI MS m/z 423 [M+H]+.

Example 49. Preparation of methoxy(4-(3-methylpiperazin yl)phenyl)quinazolin-4(3H)-—one /o o A solution of 4~acetylmethylpiperazin-1—y|)phenyl)-5,7- dimethoxyquinazolin-4(3H)—one (0.340 g, 0.80 mmol) in 2 N HCl (5 mL) was heated to reflux and stirred for 3 days. Then, the resulting solution was cooled to room temperature, basified with 2 N NaOH, ted with CH2C|2, and concentrated in vacuo. The material was ed by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrate NH4OH in CH2CI2, to afford the title compound (0.03 g, 9%). 1H NMR (300 MHz, DMSO—de): 510.76(s, 1H), 8.08 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 9.1 Hz, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.62-3.79 (m, 2H), 2.90-3.04 (m, 1H), 2.57- 2.85 (m, 4H), 2.20-2.39 (m, 1H), 1.03 (d, J = 6.3 Hz, 3H). ESI MS m/z 381 [M+H]+.

Example 50. Preparation of N—Benzyl-N-(1—(5-(5,7-dimethoxy—4~oxo-3,4— dihydroquinazolin-2—yl)pyridinyl)piperidinyl)ac:tamide <11U g; To a solution of/ten‘-buty| 4—oxopiperidine-1—carboxylate (10.0 g, 50.2 mmol) and benzylamine (2.7 mL, 25.1 mmol) in MeOH (30 mL) was added HOAc (1.9 mL, 32.6 mmol), followed by NaCNBH3 (2.0 g, 32.6 mmol) and the reaction was stirred at room temperature overnight. The resulting e was quenched with H20 (5 mL) and concentrated in vacuo. The residue was diluted with 0.1 N HCl and washed with 320. The aqueous layer was then basified with 2 N NaOH and ted with 320. The organics were washed with brine, dried over anhydrous NaZSO4, filtered, and concentrated in vacuo, to afford ten‘~butyl 4- (benzylamino)piperidinecarboxylate (8.1 g, 56%).

To a on of tert—butyl 4-(benzylamino)piperidinecarboxylate (8.1 g, 28.0 mmol) and EN (7.8 mL, 56.0 mmol) in CH2CI2 (100 mL) was added acetyl chloride (2.4 mL, 33.5 mmol) and the reaction was stirred at room temperature overnight, then concentrated in vacuo. cation by flash chromatography on silica gel, eluting with 30% to 60% EtOAc/CHZCIZ, afforded utyl 4-(N—benzylacetamido)piperidinecarboxylate (9.3 g, 99%).

A solution of tert—butyl 4~(N—benzylacetamido)piperidine-1— carboxylate (9.3 g, 28.0 mmol) in dioxane (20 mL) and 4 M HCI/dioxane (14.0 mL, 56.0 mmol) was stirred at room ature overnight and then concentrated in vacuo. The residue was basified with 2 N NaOH and extracted with EtOAc. The organics were washed with brine, dried (Na2804), filtered, and concentrated in vacuo, to afford N—benzyl-N—(piperidinyl)acetamide (4.4 g, 67%).

To a solution of N-benzyl-N-(piperidinyl)acetamide (1.5 g, 6.3 mmol) and 2—(6-chloropyridin-3—yl)-5,7—dimethoxyquinazolin~4(3H)-one (1.0 g, 3.2 mmol) in DMF (15 mL) was added K2003 (0.875 g, 6.3 mmol) and the reaction was heated at reflux temperature overnight. The ing mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CHZCIZ, to afford the title compound (0.500 g, 30%) as a white solid. 1H NMR (300 MHz, DMSO-ds): 5 11.84 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 7.33—7.37 (m, 1H), 7.14—7.27 (m, 4H), 6.88-6.96 (m, 1H), 6.66 (d, J = 1.5 Hz, 1H), 6.46 (d, J = 1.5 Hz, 1H), 4.44-4.58 (m, 4.5H), 4.10-4.20 (m, 0.5H), 3.87 (s, 3H), 3.83 (s, 3H), .98 (m, 2H), 2.25 (s, 1.5H), 1.95 (s, 1.5H), 1.45- 1.77 (m, 4H). ESI/APCl MS m/z 514 [M+H]+.

Example 51. Preparation of 2~(6—(4-(Benzylamino)piperidin-1—yl)pyrldin—3—yl)—5,7- dimethoxyquinazolin-4(3H)—one /OmN\ / N /o o A solution of N-benzyl-N-(1—(5-(5,7—dimethoxy-4—oxo-3,4- dihydroquinazolinyl)pyridin~2~yl)piperidinyl)acetamide (0.200 g, 0.39 mmol) in 2 N HCl (15 mL) was refluxed for 3 days. The resulting mixture was basified with 2 N NaOH and extracted with CHZCIZ. The organics were washed with brine, dried over anhydrous NaZSO4, filtered, and trated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 100% of 92:7:1 MeOH/concentrated NH4OH in CHZClz, ed the title compound (0.110 g, 60%) as a white solid. 1H NMR (300 MHz, DMSO—ds): 6 11.11 (br s, 1H), 8.89 (d, J = 2.3 Hz, 1H), 8.22—8.26 (m, 1H), 7.28-7.37 (m, 4H), 7.18-7.23 (m, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 4.27- 4.31 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.76 (s, 2H), 3.00-3.11 (m, 2H), 2.62-2.69 (m, 1H), 1.88—1.91 (m, 2H), 1.25-1.31 (m, 2H). ESI MS m/z 472 [M+H]+.

Example 52. Preparation of 4—(4-(5,7—Dimethoxy—4—oxo-3,4—dihydroquinazolin-2~ yl)phenyl)piperazine—1—carbaldehyde A mixture of methyl formate (75 mL) and 5,7-dimethoxy(4- (piperaziny|)pheny|)quinazolin—4(3H)—one (0.300 g, 0.82 mmol) was heated at reflux for 48 hours. The mixture was concentrated, and purified by silica gel tography, eluting with 1:1 CH2C|2I92:7:1 CHCI3/MeOH/concentrated NH4OH, to afford the title nd (0.320 g, 99%) as a white solid. 1H NMR (300 MHz, DMSO-ds):611.79(br s, 1H), 8.10-8.19 (m, 3H), 7.06 (d, J = 9.1 Hz, 2H), 6.69 (d, J = 2.3 Hz, 1H), 6.48 (d, J: 2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.46-3.59 (m, 4H), 3.32-3.38 (m, 4H). APCI MS m/z 393 [M-H]'.

Example 53. Preparation of 5,7-Dimethoxy—2-(4—(4-oxopiperidin-1~ yl)phenyl)pyrido[2,3—d]pyrimidin—4(3H)—one /o l" .90 / NH O O To a on of 2—[4-(4—hydroxy—piperazin—1-y|)-phenyl]—5,7- dimethoxy—3H-pyrido[2,3-d]pyrimidin—4-one (160 mg, 0.418 mmol) in DMSO (4.0 mL), 1,2—benziodexol-3(1H)—one—1-hydroxy—1-oxide (IBX) (178 mg, 0.635 mmol) was added and the reaction mixture was kept at 50 °C for 16 hours. Water was added and the precipitated solid was filtered to give crude product, which was purified by column chromatography (silica gel 0 mesh; eluting with 3% methanol in dichloromethane) to obtain the title compound as a yellow solid. Yield: 0.70 g (44.0%). MP > 350°C. 1H NMR (400 MHz, CDClg): 512.15 (s, 1H), 8.18 (d, J = 9.2 Hz, 2H), 7.02 (d, J = 9.2 Hz, 2H), 6.33 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.77 (t, J = 6.4 Hz, 4H), 2.45 (t, J = 6.4 Hz, 4H).

Example 54. Preparation of 2-(2—(Hydroxymethyl)—1 H-indolyl)—5,7— dimethoxyquinazolin—4(3H)—one /o o To a solution of N-(4~formyl-phenyl)-acetamide (1.25 g, 7.67 mmol) in trifluoroacetic acid (70 mL) was slowly added thallium(lll)trifluoroacetate (5.00 g, 9.20 mmol). The on mixture was d at room temperature for 30 minutes. Then, a solution of sodium iodide (1.19 g, 7.95 mmol) in water (10 mL) was added slowly. The color changed to dark purple and a lot of solid was formed.

Stirring continued at room temperature for 16 hours. Solvent was ated to half of the volume, and water (50 mL) was added. The pH was adjusted to approximately 13 with 4 N NaOH solution. The mixture was extracted with ethyl acetate (2X100 mL). The organic phase was dried over anhydrous Na2$O4 and concentrated on a rotary evaporator. The solid obtained was washed with ethyl acetate (2X5 mL), ether (2X10 mL), and dried under vacuum to give N-(4-formyl iodo-phenyl)—acetamide as an off-white solid. Yield: 0.760 g (34%).

To a degassed solution of N—(4—formyliodo-phenyl)—acetamide (0.760 g, 2.63 mmol) in ous DMF (20 mL) were added bis(triphenylphosphine)palladium(ll) dichloride (90 mg, 0.13 mmol), copper (I) iodide (0.03 g, 0.13 mmol), 1,1,3,3—tetramethyl ine (1.51 g, 13.1 mmol), and propargyl alcohol (0.210 g, 3.68 mmol). The reaction mixture was stirred at room temperature for 2 hours and then at 80 °C for 24 hours under nitrogen. Solvent was evaporated under reduced pressure. Water (100 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic phase was backwashed with water (2X100 mL), brine (100 mL), and dried over anhydrous Na2804. Solvent was evaporated and crude nd was purified by the Simpliflash system (60% ethyl acetate in hexanes as eluent) to give 2- hydroxymethyl-1H—indolecarbaldehyde as a pale yellow solid. Yield: 0.10 g (22%).

To a solution of 2-hydroxymethyl-1H—indole-5—carbaldehyde (90 mg, 0.51 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.15 g, 0.77 mmol) in MN— dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt%) (0.14 g, 0.77 mmol) and enesulfonic acid (20 mg, 0.10 mmol). The reaction mixture was stirred at 120 °C for 16 hours under nitrogen, cooled to room temperature, and concentrated under reduced pressure. Water (20 mL) was added. The separated solid was filtered, washed with water (20 mL) and ether (20 mL), and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230—400 mesh; 0-5% methanol in CH2C|2 as eluent), to give the title compound as an off-white solid. Yield: 0.06 g (33%). MP 264—265°C. 1H NMR (400 MHz, DMSO-ds):811.85(br s, 1H), 11.36 (s, 1H), 8.39 (s, 1H), 7.93 (dd, J = 8.6 and 1.6 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.41 (s, 1H). 5.34 (t, J = 5.8 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H).

Example 55. Preparation of 2-Hydroxyethyl)—1 H—indolyi)-5,7- oxyquinazolin-4(3H)—one N OH To a stirred solution of 4—aminoiodo—benzoic acid methyl ester (11.1 g, 40.0 mmol) in pyridine (80 mL) was added acetyl chloride (3.30 g, 42.0 mmol) at 0 °C under nitrogen. Stirring continued at 0 °C for 30 minutes. The ice- bath was removed, and stirring ued at room temperature for 16 hours.

Pyridine was evaporated under reduced pressure. The residue was taken in ethyl acetate (300 mL). The organic phase was washed with 2 N s HCl (200 mL), water (200 mL), brine (200 mL), and then dried over ous NaZSO4.

Removal of solvent gave 4—acetylamino—3-iodo-benzoic acid methyl ester as a white solid. Yield: 12.71 g (99%).

Lithium aluminium hydride (2.43 g, 64.1 mmol) was taken in a dry, three-necked, round bottom flask. Anhydrous THF (80 mL) was added and cooled to -10 °C. A solution of 4—acetylaminoiodo—benzoic acid methyl ester (10.2 g, 32.0 mmol) in anhydrous THF (60 mL) was added dropwise at -10 °C over a period of 45 minutes under nitrogen. Stirring was continued at -10 °C for 1 hour.

The reaction e was quenched with saturated sodium sulfate aqueous solution. The reaction mixture was then ed, and the filtrate was concentrated.

The solid was washed with methanol. The combined organic phases were dried over ous NaZSO4. The solvent was evaporated. The crude compound was purified by the Simpliflash system (5% methanol in CH2Cl2 as eluent), to give ydroxymethyl-2—iodo——phenyl)—acetamide as a white solid. Yield: 6.36 g (68%).

To a solution of lBX (0.93 g, 3.3 mmol) in dimethylsulfoxide (3.5 mL) was added N-(4-hydroxymethyliodo-phenyl)—acetamide (0.87 g, 3.0 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added and the solid was separated by filtration, and washed with ethyl e (20 mL). The filtrate was collected and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous . Removal of solvent gave N~(4—formyliodo—phenyl)- acetamide as a light brown solid. Yield: 0.82 g (95%).

To a degassed solution of N-(4-formyliodo-phenyl)—acetamide (0.810 g, 2.82 mmol) in DMF (25 mL) and triethylamine (5 mL) were added PdCl2(PPh3)2 (0.10 g, 0.14 mmol) and copper (l) iodide (0.16 g, 0.85 mmol). A degassed solution of but-3~ynol (0.27 g, 0.29 mmol) in DMF (8 mL) and triethylamine (2 mL) was added at 80 °C over a period of 1 hour under nitrogen.

After the addition, the reaction mixture was stirred at 80 °C for 4 hours, cooled to room ature, and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2804. Removal of t gave ormyl—2—(4-hydroxy-but—1-ynyl)—phenyl]- acetamide as a brown solid. Crude yield: 0.85 g (100%). The crude material was used in next step without further purification.

To a solution of N-[4-formyl(4-hydroxy-but—1—ynyl)-phenyl]— acetamide (0.85 9, approximately 2.80 mmol) in THF (20 mL) was added a THF solution of TBAF (6.0 mL, 6.0 mmol) and the reaction mixture was stirred at reflux for 36 hours under nitrogen and cooled to room temperature. Solvent was evaporated and the residue was taken in ethyl acetate (200 mL). The organic phase was washed with water (2X100 mL), brine (100 mL) and dried over anhydrous . Solvent was evaporated; crude compound was purified by simpliflash system (50% ethyl acetate in hexanes as eluent) to give ydroxy— ethyl)-1H—indole—5—carbaldehyde as yellow solid. Yield: 0.31 g (58% for two steps).

To a solution of 2-(2-hydroxy-ethyl)-1H—indole—5—carbaldehyde (0.300 g, 1.58 mmol) and o—4,6-dimethoxy—benzamide (0.370 g, 1.90 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt%) (0.350 g, 1.90 mmol) and p—toluenesulfonic acid monohydrate (60 mg, 0.32 mmol). The reaction mixture was d at 120 °C for 16 hours under nitrogen and cooled to room temperature. The solvent was evaporated under reduced pressure. Water (20 mL) was added and the solid was separated by filtration, washed with water (30 mL) and dried under vacuum. Crude compound was purified by the Simpliflash system (5:20:75 methanol / ethyl e / CH2Cl2 as eluent) to give the title nd as an off-white solid. Yield: 0.22 g (38%). MP 237-238°C. 1H NMR (400 MHz, DMSO—ds): 8 11.83 (br s, 1H), 11.20 (s, 1H), 8.34 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.37 (d, J: 8.6 Hz, 1H), 6.73 (d, J: 1.9 Hz, 1H), 6.48 (d, J :19 Hz, 1H), 6.30 (s, 1H), 4.81 (t, J = 5.1 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.75 (q, J = 6.63 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H).

Example 56. ation of 5,7—Dimethoxy(2-(pyrrolidinylmethyl)—1H-indol— -yl)quinazolin-4(3H)-one To a mixture of 5-bromo-1H—indole—2-carboxylic acid (1.0 g, 4.2 mmol), 1-ethyl(3'—dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.1 g, 5.9 mmol), 1—hydroxybenzotriazole hydrate (HOBt) (0.62 g, 4.6 mmol) in THF (20 mL) was added 4~methylmorpholine (NMM) (0.65 mL, 5.9 mmol). After 10 minutes, pyrrolidine (0.73 mL, 8.8 mmol) was added. The mixture was stirred at room temperature under nitrogen for 17 hours. The solvent was removed under reduced pressure. Water was added, stirred for 0.5 hours. The solid was filtered, washed with water, and dried in air to afford (5-bromo-1H—indol—2—yl)-pyrrolidin—1- yl—methanone as a pale yellow solid. Yield: 1.2 g (95%).

To a suspension of mo-1H—indol—2-yl)—pyrrolidinyl- methanone (0.53 g, 1.8 mmol) in THF (50 mL) at 0 °C was slowly added lithium aluminum hydride (0.20 g, 5.4 mmol). The mixture was stirred under nitrogen at 0 °C for a while and the cooling bath was allowed to warm to room temperature. The mixture was then stirred at room temperature for 17 hours. The reaction was quenched by careful, successive, dropwise addition of water (0.2 mL), 15% NaOH aqueous solution (0.2 mL), and water (0.6 mL). The solid was filtered and washed with MeOH and CHzClg. The filtrate was trated to dryness, and dried under , to give 5-bromo—2-pyrrolidin—1-ylmethyl-1H—indole as a white solid. Yield: 0.45 g (90%).

To a suspension of potassium hydride (30 wt% dispersion in mineral oil) (96 mg, 0.72 mmol) in ether (20 mL) at 0°C was added o-2—pyrrolidin-1— ylmethyl—1H—indole (0.20 g, 0.72 mmol). After stirring for 30 minutes, the reaction mixture was cooled to -78 °C, and t—BuLi solution (1.7 M in pentane; 0.93 mL, 1.58 mmol) was added. The mixture was stirred at -78 °C for 15 minutes, then at —20 °C for apporximately 3 min, and then it was cooled down to -78 °C again. DMF was added. The e was d under nitrogen at -78 °C for a while and the cooling bath was d to warm to room temperature. Saturated NaHCOs aqueous solution (approximately 5 mL) was added. The mixture was extracted with dichloromethane. The organic solution was dried over Na2804, and concentrated to s to afford a mixture of the desired product and starting material, at about a 1:1 ratio, from the NMR spectrum. The crude product (approximately 0.2 g) was used for next reaction without any further purification.

A mixture of 2—amino-4,6—dimethoxy-benzamide (0.20 g, 1.0 mmol), crude 2-pyrrolidin—1-ylmethyl-1H—indolecarbaldehyde (0.23 g, 1.0 mmol), p- toluenesulfonic acid monohydrate (0.38 g, 2.0 mmol), and sodium bisulfite (0.42 g, 4.0 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 115 °C under N2 for 17 hours and cooled to room temperature. The mixture was d with saturated Na2C03 aqueous solution and concentrated to s under reduced pressure.

The residue was purified by column chromatography on silica gel, eluting with CH2Cl227.0 M NH3 in MeOH (95:5), to afford the title compound as a yellow solid.

Yield: 87 mg (22%). MP 168—169.5°C (decomposition). 1H NMR (400 MHz, CDCI3): 8 9.05 (s, 1H), 8.22 (s, 1H), 7.85 (d, 1H), 7.43 (d, 1H), 6.84 (s, 1H), 8.45 (s, 1H), 6.43 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.81 (s, 2H), 2.57 (m, 4H), 1.81 (m, 4H). e 57. Preparation of 2—(3—(Hydroxymethyl)—1 H-indazoIyl)-5,7— oxyquinazolin-4(3H)—one To a solution of sodium nitrite (20.0 9, 290.0 mmol) in THF (1000 mL) and water (50 mL) was added 1H—indolecarboxylic acid methyl ester (5.00 g, 28.5 mmol). The mixture was cooled to 0 °C and aqueous 6 N HCI (70 mL) was added dropwise at 0 °C. After stirring for 3 days at room temperature, solvent was evaporated, and extracted with ethyl acetate (3XZ00 mL). The combined organic phase was washed brine (200 mL) and dried over ous Na2804. The solvent was evaporated. The residue was purified by the Simpliflash system (20—30% ethyl acetate in s as eluent), to give yl—1H-indazolecarboxylic acid methyl ester as a yellow solid. Yield: 1.47 g, (25%).

To a solution of 3-formyl—1H-indazolecarboxylic acid methyl ester (0.37 g, 1.80 mmol) in anhydrous methanol (15 mL) was added sodium borohydride (68 mg, 1.80 mmol) in small portions at 0°C. After the addition, the reaction mixture was stirred at 0 °C for 30 minutes. Solvent was evaporated; water (100 mL) was added and the mixture was extracted with ethyl acetate (150 mL).

The organic phase was washed with brine (100 mL) and dried over anhydrous NaZSO4. Solvent was ated to give 3-hydroxymethyl-1H-indazole carboxylic acid methyl ester as a yellow solid. Yield: 0.32 g (87%).

To a solution of 3-hydroxymethyl-1H~indazole—5-carboxylic acid methyl ester (0.32 g, 1.55 mmol) in a mixture of anhydrous dichloromethane and THF (2:1, 60 mL) was added pyridinium p-toluene sulfonate (0.08 g, 0.31 mmol) and then 3,4-dihydro—2H—pyran (0.19 g, 2.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Solvent was evaporated; water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous NaZSO4. Removal of solvent gave 3-(tetrahydro-pyran-2— ethyl)-1H—indazole—5-carboxylic acid methyl ester as a yellow gummy material. Yield: 0.55 g (crude). This product was used in next step without further 3-(Tetrahydro-pyran—2-yloxymethyl)—1H-indazolecarboxylic acid methyl ester (0.53 g crude, approximately 1.55 mmol) was taken in anhydrous THF (20 mL) and cooled to -10 °C. A solution of lithium aluminium hydride (1.0 M solution in THF, 0.12 g, 3.10 mmol) was added drop-wise at -10 °C over a period of 15 minutes under nitrogen. ng continued at -10 °C for 1 hour and the reaction was then allowed to warm to room temperature and stirring continued at room temperature for 16 hours. The reaction mixture was carefully quenched with saturated aq. saturated um chloride solution (100 mL). Then, reaction e was diluted with ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL) and dried over anhydrous NaZSO4. Solvent was evaporated to give [3—(tetrahydro—pyranyloxymethyl)-1H-indazolyl]- methanol as a yellow gummy material. Yield: 0.40 g (crude). This product was used in the next step t further purification.

To a solution of [3—(tetrahydro-pyranyloxymethyl)-1H—indazolyl]- methanol (0.40 g, 1.50 mmol) in DMSO (3 mL), IBX (0.42 g, 1.50 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours under nitrogen. Water (50 mL) was added; the separated solid was filtered, and the solid was washed with ethyl acetate (100 mL). The filtrate was collected and the organic phase was separated, washed with brine (100 mL), and dried over anhydrous NaZSO4. Removal of solvent gave 3-(tetrahydro-pyran—2-yloxymethyl)- azole-5~carbaldehyde as an off-white solid. Yield: 0.33 g (84%).

To a solution of 3-(tetrahydro—pyran—2-yloxymethyl)—1H-indazole carbaldehyde (0.32 g, 1.23 mmol) and 2-amino—4,6—dimethoxy-benzamide (0.24 g, 1.23 mmol) in N,N-dimethylacetamide (10 mL) were added NaH803 (58.5 wt%, 0.27 g, 1.48 mmol) and p-toluenesulfonic acid monohydrate (0.05 g, 0.25 mmol); the on mixture was heated at 120 °C for 16 hours, then cooled to room temperature. Solvent was removed under d pressure. The residue was diluted with water (100 mL). The separated solid was filtered and washed with water and dried under vacuum. The residue was purified by the Simpliflash system (05% methanol in CH2C|2 as eluent) to give the title compound as an off- white solid. Yield: 30 mg (7%). MP 264-266°C. 1H NMR (400 MHz, CD30D): 6 8.60 (s, 1H), 8.10 (d, J = 8.98 Hz, 1H), 7.65 (d, J = 8.98 Hz, 1H), 6.85 (d, J = 1.95 Hz, 1H), 6.55 (d, J = 1.95 Hz, 1H), 5.05 (s, 2H), 3.96 (s, 6H).

Example 58. Preparation of methoxy—2-(2—(2-(pyrrolidinyl)ethyl)—1H—indol- -yl)quinazolin-4(3H)—one a N3 To a stirred on of 4-amino-3—iodo-benzoic acid methyl ester (11.1 g, 40.0 mmol) in anhydrous pyridine (80 mL) was added acetyl chloride (3.30 g, 42.0 mmol) at 0 °C under nitrogen. Stirring was continued at 0 °C for 30 minuntes. The th was removed, and ng continued at room temperature for 16 hours. Pyridine was evaporated under reduced pressure. The residue was taken in ethyl acetate (300 mL). The organic phase washed with 2 N aqueous HCl (200 mL), water (200 mL), brine (200 mL), and was dried over anhydrous NaZSO4.

Removal of solvent gave ylamino-3—iodo-benzoic acid methyl ester as a white solid. Yield: 12.7 g (99%).

To butynol (40.0 9, 570.0 mmol) and hydro-2H-pyran (48.0 9, 570.0 mmol) in anhydrous dichloromethane (350 mL) was added pyridium p-toluenesulfonate (0.45 g, 1.80 mmol). The mixture was stirred at room temperature for 16 hours. Solvent was evaporated, and the residue was purified by vacuum distillation to give 2-but—3—ynyloxy-tetrahydro-pyran as a light yellow liquid. Yield: 60.0 g (68%).

To a degassed solution of 4—acetylamino—3—iodo—benzoic acid methyl ester (41.4 g, 130 mmol) in DMF (200 mL) and triethylamine (40 mL) were added PdCl2(PPh3)2 (3.99 g, 5.68 mmol) and copper (I) iodide (7.43 g, 39.0 mmol). A degassed solution of 2-butynyloxy-tetrahydro-pyran (30.1 g, 195 mmol) in DMF (100 mL) and triethylamine (20 mL) was added at 80 °C over a period of 1 hour under nitrogen. After the on, the reaction mixture was stirred at 80 °C for 2 hours and then cooled to room temperature. Solvent was evaporated under reduced pressure. Ethyl acetate (200 mL) was added. The solid was filtered, and washed with ethyl acetate. The ethyl acetate solution was washed with brine, and dried over anhydrous Na2804. The organic phase was trated to dryness, to afford 66.8 g crude 4-acetylamino-3—[4—(tetrahydro-pyranyloxy)—butyny|]- benzoic acid methyl ester. This was used in next step without further purification.

A solution of crude 4-acetyiamino—3-[4—(tetrahydro-pyranyloxy)- ynyI]—benzoic acid methyl ester (33.4 9, approximately 65 mmol) in anhydrous THF (300 mL) was mixed with a 1.0 M solution of tetrabutylammonium fluoride in THF (110 mL, 110 mmol); the reaction mixture was stirred at 90 °C for 4 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated and the e was taken in ethyl acetate (300 mL). The organic phase was washed with water (300 mL), brine (200 mL), and dried over anhydrous NaZSO4. The t was evaporated and the crude compound was purified by column chromatography on silica gel, eluting with hexanes and ethyl acetate (3:1), to give tetrahydro-pyranyloxy)—ethy|]-1H—indolecarboxylic acid methyl ester. Yield: 14.9 g (76%).

Lithium aluminum hydride (3.38 g, 89.0 mmol) in ous THF (100 mL) was cooled to -30 °C. 2-[2-(Tetrahydro—pyran-2—yloxy)-ethyI]-1H—indole- -carboxylic acid methyl ester (13.5 g, 44.5 mmol) in anhydrous THF (100 mL) was added dropwise. The reaction mixture was stirred at -20 °C for 1 hour and then at room temperature for 4 hours. The reaction mixture was cooled to 0 °C and water (6 mL) was added slowly. Ammonium chloride solution (200 mL) was added and extracted with ethyl acetate (2XZ00 mL). The organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated to give {2—[2-(tetrahydro-pyran—2- yloxy)-ethyl]-1H-indoi—5—yl}—methanol as a white solid. Yield: 11.50 g (94%).

(Tetrahydro-pyran—2-yloxy)-ethyl]-1H~indo|—5-y|}-methanoi (1 1.5 g 41.7 mmol) in anhydrous DMSO (45 mL) was added iBX (12.3 g, 43.8 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL), the organic phase was washed with water, then brine, and was purified by column chromatography on silica gel, g with dichloromethane, to give 2-[2- (tetrahydro-pyran—2—yloxy)—ethyl]-1H—indole—5—carbaldehyde as a white solid. Yield: 8.50 g (75%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (6.10 g, 31.1 mmol) and 2-[2-(tetrahydro—pyranyloxy)—ethyl]—1H—indolecarbaldehyde (8.50 g, 31.1 mmol) in N,N—dimethylacetamide (45 mL) was added NaH803 (58.5 wt%, 6.08 g, 34.2 mmol) and p-TSA (0.60 g, 3.11 mmol). The reaction mixture was heated at 115 °C for 16 hours and then cooled to room temperature. N,N- dimethylacetamide was removed under reduced re, the residue was diluted with water (50 mL) and the solid was collected and mixed with dichloromethane (100 mL), ether (100 mL), and then filtered to give a mixture of 5,7~dimethoxy (tetrahydro—pyranyloxy)—ethyl]~1H-indolyl}—3H—quinazolin—4-one and 2— [2-(2—hydroxy—ethyl)-1H—indolyl]-5,7-dimethoxy-3H—quinazolinone as a white solid, which was used in next step without further purification. Yield: 7.50 g (crude).

A mixture of 5,7—dimethoxy{2—[2-(tetrahydro-pyran—2—yloxy)-ethyl]- 1H—indol—5—yl}-3H—quinazolinone and 2-[2-(2—hydroxy-ethyl)—1H—indolyl]-5,7- dimethoxy-3H-quinazolinone (7.50 g, 16.6 mmol) was dissolved in anhydrous methanol (60 mL). 1.0 M HCI in ether (42 mL) was added and the reaction was stirred at room temperature for 2 hours. The solid was filtered and the mother liquor was ated to dryness and the e was combined with the solid.

Sodium bicarbonate solution (200 mL) was added and d for 1 hours. The separated solid was ed and washed with cold water and dried under vacuum to give 2—[2-(2-hydroxy—ethyI)—1H—indol—5-yl]-5,7-dimethoxy-3H—quinazolin-4—one as a white solid. Yield: 6.2 g (55%; 3 steps).

To a solution of 2-[2-(2—hydroxy-ethyl)—1H—indolyl]-5,7-dimethoxy- 3H—quinazolinone (6.20 g, 16.9 mmol) in anhydrous DMF (25 mL) was added carbon tetrabromide (6.47 g, 19.5 mmol) and triphenylphosphine (5.11 g, 19.5 mmol). The reaction mixture was stirred at 40 °C for 16 hours. DMF was removed under vacuum and water (150 mL) was added. The separated solid was filtered and mixed with ether (150 mL) and heated for 10 minutes. The solid was filtered and dried under vacuum to give 2-[2-(2—bromo—ethyl)—1H—indolyl]—5,7-dimethoxy- 3H—quinazolin—4-one as a white solid. Yield: 6.1 g (84%).

To a solution of 2-[2-(2~bromo-ethyl)—1H—indolyl]—5,7-dimethoxy- nazoiinone (6.10 g, 14.2 mmol) in anhydrous DMF (45 mL) was added pyrrolidine (6.07 g, 85.4 mmol) and the reaction mixture was stirred at 45 °C for 15 hours. DMF was removed under d pressure, the residue was taken in water (150 mL), and stirred for 30 minutes. Separated solid was filtered, washed with water, and dried under vacuum. Crude compound was purified by column chromatography (silica gel 0 mesh, eluting with 5% 7.0 M ammonia in methanol on in dichloromethane) to give the title compound as a white solid.

Yield: 3.4 g (57%). MP 215-217°C. 1H NMR (400 MHz, DMSO-de): 611.79 (s, 1H), 11.21(s, 1H), 8.31 (s, 1H), 7.88 (dd, J = 8.8 and 1.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.28 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.89 (t, J = 8.0 Hz,2H), 2.74 (t, J = 8.0 Hz, 2H), 2.48 (m, 4H), 1.67 (m, 4H).

Example 59. Preparation of 2—(2—((Dimethylamino)methyl)-1H-indoI-5—yI)—5,7— dimethoxyquinazolin-4(3H)-one /O O To a solution of 5-bromo—1H—indole-2—carboxylic acid (2.40 g, 10.0 mmol) in THF (100 mL) were added EDCl (2.11 g, 30.0 mmol), HOBt (1.49 g, 11.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes.

Then, a solution of N,N—dimethyl amine (2.0 M solution in THF, 15 mL, 30.0 mmol) was added. The mixture was stirred for 16 hours at room temperature. Solvent was evaporated, the residue was taken in ethyl acetate (200 mL), and water (200 mL) was added. The organic phase was ted; the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium e. Solvent was evaporated and dried under vacuum to give 5-bromo-1H— indolecarboxylic acid dimethylamide as an off-white solid. Yield: 2.56 g (96%). o-1H—indolecarboxylic acid dimethylamide (1.34 g, 5.00 mmol) was taken in anhydrous THF (50 mL) (suspension), and cooled to -20 °C. A solution of lithium ium hydride (1.0 M solution in THF, 10.0 mL, 10.0 mmol) was added dropwise at —20 °C over a period of 15 minutes under nitrogen, and allowed to warm to 10 °C; stirring was ued at 10 °C for 1 hour. The reaction mixture was carefully quenched with aq. ted ammonium de solution (10 mL). The reaction mixture was diluted with ethyl acetate (150 mL). The organic phase was ted, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2804. Solvent was evaporated, to give mo-1H— indoleylmethyl)—dimethyl amine as an off-white solid. Yield: 1.27 g ).

To a cold (0 °C) solution of potassium hydride (suspension in mineral oil, 0.79 g, 5.90 mmol) in anhydrous THF (60 mL) was added a solution of (5-bromo-1H—indoieylmethyl)—dimethyl amine (1.24 g, 4.90 mmol) in anhydrous THF (20 mL) was added se at 0 °C over a period of 15 minutes under nitrogen. Stirring was continued for 30 minutes at 0 °C, then cooled to -10 °C. n- Butyl lithium (1.6 M solution in hexanes, 7.4 mL, 11.7 mmol) was added rapidly.

Stirring was continued at —10°C for 1 h. Then, anhydrous DMF (5.0 mL) was added, and the mixture was d to warm to room temperature over 2 h. The reaction mixture was carefully quenched with 1N aq. HCl (10 mL). The reaction mixture was diluted with ethyl acetate (150 mL). The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous NaZSO4. The t was ated to give 2-dimethylaminomethyl- 1H—indole—5-carbaldehyde as an orange~colored gummy material. Yield: 0.91 g (crude). This product was used in next step without further purification.

To a solution of 2-dimethylaminomethyI-1H—indolecarbaldehyde (0.88 g crude, 4.35 mmol) and 2—amino—4,6-dimethoxy-benzamide (0.85 g, 4.35 mmol) in N,N—dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt%, 0.95 g, 5.22 mmol) and p-toluenesulfonic acid (0.99 g, 5.22 mmol).

The reaction mixture was stirred at 120 °C for 5 hours under nitrogen, then cooled to room temperature, and concentrated under reduced pressure. 30% aqueous sodium carbonate (50 mL) was then added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was purified by the Simpliflash system (0-5°/o methanol in CH2C|2 and 7 N ammonia in methanol 5% in CHZClz as eluent) to give the title compound as an off-white solid.

Yield: 0.83 g (50%). MP 187-188°C. 1H NMR (400 MHz, DMSO-ds): 8 11.82 (s, 1H), 11.34 (s, 1H), 8.38 (s, 1H), 7.93 (d, J = 8.59 Hz, 1H), 7.40 (d, J = 8.59 Hz, 1H), 6.73 (s, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.57 (s, 2H), 2.21 (s, 6H).

Example 60. Preparation of N-(4-(5,7-Dimethoxy—4-oxo—3,4-dihydroquinazolin yl)phenyl)methanesulfonamide A mixture of obenzaldehyde (0.250 g, 1.40 mmol), methanesulfonamide (0.154 g, 1.62 mmol), copper iodide (0.0510 g, 0.270 mmol), N,N-dimethylglycine (0.0280 g, 0.270 mmol), and ium phosphate tribaslc (0.716 g, 3.38 mmol) in DMF (5.00 mL) was stirred at reflux for 16 hours. The mixture was diluted with EtOAc (50 mL), washed with water (50 mL), and then saturated aqueous LiCl (5 mL). The ed aqueous layers were then back- extracted with EtOAc (50 mL). The c layers were combined, washed with brine (50 mL), dried over NaZSO4, filtered, and the solvent was removed under reduced pressure, to provide N-(4—formylphenyl)methanesulfonamide (0.161 g, 58%) as a yellow oil.

A mixture of N—(4-formylphenyl)methanesulfonamide (0.161 9, 0.0800 mmol), 2-amino—4,6-dimethoxybenzamide (0.159 g, 0.0800 mmol), NaH803 (94%, 0.00460 9, 0.0240 mmol), and p—TsOH-HZO (0.0125 g, 0.120 mmol) in DMA (1.00 mL) was heated at 155 °C for 16 hours. The mixture was diluted with EtOAc (50 mL), washed with water (2XSO mL), then brine (50 mL), dried over N82804, filtered, and the solvent was removed under . The residue was purified over silica gel (12 g, CH2Cl2/MeOH) and the product was freeze-dried from MeCN/H20 to provide the title compound (0.0341 g, 11%) as a pale yellow solid. 1H NMR (300 MHz, DMSO—de): 8 11.94 (s, 1H), 10.21 (s, 1H), 8.16 (d, J = 8.76 Hz, 2H), 7.30 (d, J = 8.76 Hz, 2H), 6.72 (d, J = 2.25 Hz, 1H), 6.52 (d, J = 2.25 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.09 (s, 3H). MS (ESI) m/z 376 [C17H17N305S+H]+.

Example 61. Preparation of methoxy—2-(4-(pyridin—4— ylamino)phenyl)quinazolin—4(3H)-one 0 O A mixture of compound 2-(4-bromophenyl)—5,7-dimethoxyquinazolin— 4(3H)—one) (0.200 g, 0.554 mmol), 4-aminopyridine (0.0573 g, 0.609 mmol), Pd2(dba)3 (0.0025 9, 0.0028 mmol), Xantphos (0.0018 9, 0.0031 mmol), and Cs2003 (0.253 g, 0.776 mmol) in 1,4-dioxane (2.22 mL) under nitrogen was heated at 105 °C for 2 days. The mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with water (3X75 mL), then brine (75 mL), dried over anhydrous NaZSO4, ed, and the solvent was removed under vacuum.

The resulting residue was purified over silica gel (12 g, EtOAc/CHCI3/MeOH/NH4OH), to provide the title nd compound as a white solid. 1H NMR (300 MHz, DMSO-de):511.90(s, 1H), 9.19 (s, 1H), 8.29 (d, J = 6.29 Hz, 2H), 8.17 (d, J = 8.75 Hz, 2H), 7.30 (d, J = 8.75 Hz, 2H), 7.05 (d, J = 6.29 Hz, 2H), 6.72 (d, J = 2.26 Hz, 1H), 6.51 (d, J = 2.26 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ESI) m/z 375 [C21H18N403+H]+.

Example 62. Preparation of 5,7-Dimethoxy(4-(p-tolylamino)phenyl)quinazolin— 4(3H)-one /0\::[::\(©( QNH N To a mixture of Pd(OAc)2 (0.0112 9, 0.0166 mmol) and (S)—(—)— BINAP (0.0155 9, 0.0249 mmol) was added a degassed solution of toluene/t- BuOH (5:1, 3.00 mL) and the mixture was heated at 100 °C for 1 minute. ln a second flask, 2~(4-bromophenyl)-5,7—dimethoxyquinazolin-4(3H)—one) (0.300 g, 0.831 mmol) and degassed toluene/t—BuOH (5:1, 4.00 mL) was heated at 100 °C for 1 minute, t—BuOK (0.130 g, 1.17 mmol) was added, and the e heated until most of the solids dissolved. This mixture was then cooled, additional t—BuOK (0.130 g, 1.17 mmol) was added, followed by p-toluidine (0.107 g, 0.997 mmol), the Pd catalyst/ligand mixture, and additional toluene/t—BuOH (5:1, 3.00 mL). The reaction was heated at 105 °C for 3 days, then cooled to room temperature, diluted with water (100 mL), and ted with EtOAc (2X1OO mL). The combined organic layers were washed with brine (50 mL), dried over , filtered, and the solvent was removed under . The resulting residue was purified over silica gel (4 g, CHQCIZIMeOH) and the product was freeze—dried from MeCN/Hgo to provide the title nd (0.0212 g, 6%) as a yellow solid. 1H NMR (300 MHz, DMSO-ds):811.71 (s, 1H), 8.54 (s, 1H), 8.06 (d, J = 8.82 Hz, 2H), 7.18—6.99 (m, 6H), 6.67 (d, J = 2.21 Hz, 1H), 6.47 (d, J = 2.21 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H). MS (ESI) m/z 388 [C23H21N303+H]+.

Example 63. Preparation of 5,7-Dimethoxy—2—(4—(pyridin ylamino)phenyl)quinazolin-4(3H)—one A mixture of 2-(4—bromophenyl)—5,7-dimethoxyquinazolin—4(3H)—one (0.200 g, 0.55 mmol), 3—aminopyridine (0.057 g, 0.61 mmol), Cs2C03 (0.253 g, 0.776 mmol), Xantphos (0.002 g, 0.003 mmol), and Pd2(dba)3 (0.003 g, 0.003 mmol) in dioxane (2 mL) were ed in a microwave tube under nitrogen and irradiated at 300 W, 105 °C for 30 minutes. Then, DMF (1 mL) was added and the flask was irradiated for 1 hour at 300 W, 105 °C. Then, the mixture was concentrated and purified by silica gel chromatography, eluting with 922711 CHCI3/MeOH/concentrated NH4OH. The residue was r purified by reverse- phase HPLC, eluting with 10% to 90% CH3CN in H20 with 0.1% TFA, to afford the title compound (0.105 g, 51%) as a white solid. 1H NMR (300 MHz, DMSO-ds): 8 11.83 (s, 1H), 8.82 (s, 1H), 8.44 (d, J: 2.4 Hz, 1H), 8.11-8.16 (m, 3H), 7.59-7.62 (m, 1H), 7.31-7.35 (m, 1H), 7.13 (d, J: 8.7 Hz, 2H), 6.68 (d, J = 1.8 Hz, 1H), 6.46 (d, J: 1.8 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H). APCI MS m/z 375 [M+H]+.

Example 64. Preparation of 4-(4-(5,7-Dimethoxyoxo-3,4—dihydroquinazolin yl)phenoxy)—N,N—dimethylpiperidinecarboxamide / \quH\ \n/\ To a on of 4—hydroxypiperidine (5.0 g, 49 mmol) in THF (70 mL) was added triethylamine (14.4 mL, 103 mmol) and dimethylcarbamyl chloride (9.0 mL, 98 mmol) slowly. The mixture was stirred at room temperature for 1.5 hours.

The white itate was filtered off, washed with THF. The THF solution was concentrated to dryness then purified with column tography (SiOz, MeOH / CH2Cl2 = 1:19) to afford 4-hydroxypiperidinecarboxylic acid ylamide as colorless oil. Yield: 7.8 g (94%). 4-Hydroxypiperidinecarboxylic acid dimethylamide (1.45 g, 8.40 mmol), 4—hydroxbenzenaldehyde (1.02 g, 8.40 mmol) and triphenylphosphine (3.31 g, 12.6 mmol) were stirred in THF (6 mL). Diisopropylazodicarboxylate (2.51 mL, 12.6 mmol) was added dropwise to the reaction mixture at room temperature over the course of 5 minutes. The mixture was stirred at room temperature for 21 hours, concentrated, and purified by column chromatography (SiOz, hexanes/ ethyl acetate = 1:1 to neat ethyl acetate), to afford 4-(4-formylphenoxy)—piperidine— 1-carboxylic acid dimethylamide a white solid. Yield: 0.7 g (30%).

To a 100 mL round-bottom flask was added 2-amino-4,6— dimethoxybenzamide (196 mg, 1.00 mmol), ormylphenoxy)-piperidine carboxylic acid dimethylamide (300 mg, 1.10 mmol), p—toluenesulfonic acid monohydrate (21 mg, 0.10 mmol), sodium hydrogensulfite (216 mg, 1.20 mmol) and dimethylacetamide (5 mL). The mixture was stirred at 115 °C under N2 for 17 hours and cooled to room ature. Water (20 mL) was added and stirred for 0.5 hours. The precipitate was filtered off, washed with water, and air dried. The crude product was purified by column chromatography (SiOz, neat ethyl acetate, then ethyl acetate / methanol = 19:1, then CHZClg / methanol = 19:1) to afford the title compound as a white solid. Yield: 110 mg (24%). MP 248-249°C. 1H NMR (400 MHz, DMSO-ds):511.91 (s, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.10 (d, J: 8.8 Hz, 2H), 6.72 (s, 1H), 6.51 (s, 1H), 4.71-4.69 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), .39 (m, 2H), 3.06-2.99 (m, 2H), 2.74 (s, 6H), 2.00—1.96 (m, 2H), 1.64-1.59 (m, 2H).

Example 65. Preparation of 2-(4—(1—Acetylpiperidinyloxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)—one /0 Nfl UV /o o To a solution of 4—hydroxypiperidine (5.00 g, 49.4 mmol) in anhydrous THF (30 mL) and triethylamine (10 mL, 75 mmol) was added acetyl de (3.52 mL, 49.4 mmol). After the addition, the mixture was stirred for another 2 hours at room temperature. The solid formed was filtered and the mother liquid was concentrated to yield 5.0 g of crude t, which was purified by column chromatography on silica gel (230-400 mesh), using 5% methanol in dichloromethane as , to give 1—(4-hydroxy-piperidin~1—yl)-ethanone. Yield: 2.40 g (34%).

To a solution of 1-(4-hydroxy-piperidiny|)-ethanone (1.00 g, 6.90 mmol), 4-hydroxybenzaldehyde (0.854 g, 6.90 mmol) and nylphosphine (1.83 g, 6.90 mmol) in THF (10 mL) was added dropwise diisopropyl arboxylate (DIAD) (1.41 g, 6.90 mmol). The reaction mixture was stirred at room temperature for 16 hours, THF was evaporated, and the residue was purified by column chromatography, using dichloromethanezethyl acetate2methanol (1 22005) as eluent, to give 4—(1~acetyl-piperidinyloxy)- benzaldehyde. Yield: 0.40 g (23%).

To a solution of o-4, 6-dimethoxy—benzamide (0.20 g, 1.0 mmol) and 4-(1-acetyl-piperidinyloxy)—benzaldehyde (0.259, 1.0 mmol) in N, N- dimethyl acetamide (5 mL), NaHSO3 (0.209, 1.1 mmol) and p-TSA (20 mg, 0.10 mmol) were added and the reaction mixture was heated at 115 °C for 16 hours.

The reaction mixture was cooled to room temperature. N,N-dimethylacetamide was removed under reduced re. The residue was diluted with water and the solid was collected; the crude product was purified by column chromatography on silica gel (230—400 mesh), using 5% methanol in CHZCI2 as eluent, to give the title compound. Yield: 0.2 g (47%). MP 275-277°C. 1H NMR (400 Hz, CDC|3)I 511.94 (s, 1H), 8.16 (d, 2H), 7.10 (d, 2H), 6.70 (d, 1H), 6.50 (d, 1H), 4.76 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.70 (m, 1H), 3.30 (m, 2H), 3.20 (m, 1H), 2.04 (s, 3H), 1.95 (m, 2H), 1.64 (m, 1H), 1.52 (m, 1H).

Example 66. ation of 2-(4-(2—(lsoindolin—2-yl)ethoxy)—3,5-dimethylphenyl)— methoxyquinazolin-4(3H)-one o\/\N "(2%"; Q3 /0 o To a suspension of 2-[4-(2-bromoethoxy)-3,5—dimethylphenyl]-5,7- dimethoxy-3H—quinazolin-4—one (0.50 g, 1.15 mmol) in anhydrous DMF (9 mL) was added isoindoline (0.41 mL, 3.46 mmol) and the on mixture was stirred at room temperature for 16 hours under nitrogen. The solvent Was removed under reduced pressure and the residue was triturated with water (50 mL). The separated solid was filtered, washed with water and ether, and dried under vacuum to give the title compound as a white solid. Yield: 0.45 g (83%). MP 202- C. 1H NMR (400 MHz, CDCI3): 510.09(br s, 1H), 7.77 (s, 2H), 7.22 (br s, 4H), 6.83 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 4.11 (s, 4H), 4.03 (t, J = 6.0 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.22 (t, J = 6.0 Hz, 2H), 2.42 (s, 6H).

Example 67. Preparation of 2-(3,5-Dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)—5— methoxyquinazolin-4(3H)-one N OWD Qin/NH\ To a stirred on of 2-amino~6~methoxy-benzoicacid (3.00 g, 17.9 mmol) in THF (90 mL), EDCl (7.89 g, 41.1 mmol) and HOBt (7.95 g, 51.9 mmol) were added and stirred at room temperature for 30 minutes then N- methylmorpholine (6.15 g, 60.0 mmol) and aqueous 50% v/v NH4OH (12 mL, 171.4 mmol) was added. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was extracted with ethylacetate (4X100 mL), the combined organic phase was washed with water and brine, and dried over anhydrous sodium sulfate; the solvent was evaporated to give 2-aminomethoxy—benzamide as an ite solid. Yield: 1.90 g, (65%).

To a solution of 2-aminomethoxy-benzamide (1.00 g, 6.01 mmol) and 4-(2-hydroxy-ethoxy)—3,5-dimethyl—benzaldehyde (1.28 g, 6.59 mmol) in MN- dimethylacetamide (15 mL) were added NaH803 (58.5 wt%, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heated at 115 °C for hours, and cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 h, ed, and dried under vacuum to give 2—[4-(2-hydroxy—ethoxy)— 3,5-dimethyl—phenyl]methoxy—3H—quinazolinone as an off—white solid. Yield: 1.1 g (55%).

To a solution of 2-[4—(2—hydroxy-ethoxy)—3,5-dimethyl-phenyl] methoxy3H—quinazolinone (1.10 g, 3.20 mmol) in anhydrous N,N- dimethylformamide (16 mL) were added nylphosphine (0.92 g, 3.50 mmol) and carbontetrabromide (1.17 g, 3.50 mmol). The reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230—400 mesh; 3% methanol in dichloromethane as eluent) to give 2-[4(2—bromo-ethoxy)-3,5- dimethyl-phenyl]~5—methoxy3H—quinazolin—4-one as an off-white solid. Yield: 0.60 g (46%).

To a solution of 2-[4(2—bromo~ethoxy)-3,5-dimethyl-phenyl1 methoxy3H—quinazolinone (0.50 g, 1.20 mmol) in N,N-dimethy|formamide (10 mL) was added pyrrolidine (0.53 g, 7.40 mmol) and the reaction e was stirred at room temperature for 15 hours. DMF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 230—400 mesh; 5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.25 g (52%). MP 157—158°C. 1H NMR (400 MHz, e): 6 11.95 (s, 1H), 7.89 (s, 2H), 7.70 (t, J = 8.19 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.1Hz, 1H), 3.91-3.89 (m, 2H), 3.87 (s, 3H), 2.82 (t, J = 6.2 Hz 2H), .50 (m, 4H), 2.30 (s, 6H), 1.69 (m, 4H). MS (ES+) m/z: 394.61(M+1).

Example 68. Preparation of 5,7-Dichloro-2—(3,5-dimethyl—4-(2—(pyrrolidin yl)ethoxy)phenyl)quinazolin-4(3H)-one Cimm.N Cl 0 To a solution of 2-amino—4,6—dichloro—benzoic acid (4.12 g, 20.0 mmol) in THF (120 mL) were added EDCI (4.22 g, 22.0 mmol), HOBt (2.70 g, 20.0 mmol) and N—methylmorpholine (2.22 g, 22.0 mmol). The reaction mixture was stirred at room ature for 20 minutes, then 50% (v/v) aqueous NH4OH solution (2.8 mL, 40.0 mmol) was added. The e was stirred for 20 hours at room temperature. The solvent was evaporated, the residue was taken in ethyl acetate (200 mL), and water (200 mL) was added. The organic phase was separated; the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and dried under vacuum to give 2-amino-4,6-dichloro—benzamide as an off-white solid. Yield: 3.83 g (93%).

To a solution of 2-amino-4,6—dichloro-benzamide (1.54 g, 7.50 mmol) and 4-(2-hydroxy—ethoxy)—3,5-dimethyl-benzaldehyde (1.46 g, 7.50 mmol) in methylacetamide (15 mL) were added sodium en sulfite (58.5 wt%, 1.51 g, 8.25 mmol) and p-toluenesulfonicacid monohydrate (0.28 g, 1.50 mmol). The reaction mixture was stirred at 120 °C for 16 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was r washed with ether and dried under vacuum to give 5,7-dichloro[4—(2-hydroxy- ethoxy)~3,5-dimethylphenyl]-3H—quinazolinone as a white solid. Yield: 2.42 g (85%).

To a solution of chloro-2—[4—(2-hydroxy-ethoxy)—3,5— dimethylphenyl]-3H—quinazolin~4—one (1.14 g, 3.00 mmol) in anhydrous DMF (15 mL) was added carbon tetrabromide (1.10 g, 3.30 mmol). Then, triphenylphosphine (0.86 g, 3.30 mmol) was added in small portions. The on mixture was stirred at room temperature for 16 hours under nitrogen. Solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate (50 mL) and dried under vacuum to give 2-[4-(2-bromo—ethoxy)—3,5~ dimethylphenyl]-5,7-dichIoro-3H—quinazolin-4—one as a white solid. Yield: 0.46 g (35%).

To a solution of 2—[4—(2—bromo—ethoxy)—3,5-dimethylphenyI]—5,7- dichloro-3H—quinazolinone (0.44 g, 1.00 mmol) in anhydrous DMF (10 mL) was added pyrrolidine (0.28 g, 4.00 mmol). The reaction mixture was stirred at room temperature for 6 hours under nitrogen. Solvent was evaporated under reduced pressure. Water (50 mL) was added. The separated solid was filtered, washed with water (20 mL), and dried under . The crude compound was purified by the Simpliflash system (0-5% methanol in CHzClz and 5% methanol (containing 7.0 M ammonia) in CHZCIZ as eluent) to give the title compound as a white solid.

Yield: 0.31 g (72%). MP 209-210°C. 1H NMR (400 MHz, DMSO-de):512.39(br s, 1H), 7.90 (s, 2H), 7.71 (d, J = 1.95 Hz, 1H), 7.60 (d, J =1.95 Hz, 1H), 3.91 (t, J = .85 Hz, 2H), 2.83 (t, J = 6.05 Hz, 2H), 2.55 (m, 4H), 2.31 (s, 6H), 2.01 (m, 4H).

MS (ES+) m/z 432.54 (100%), 434.49 (90%).

Example 69. Preparation of —Dimethyl(3-(pyrrolidinyl)propoxy)phenyl)- ,7-dimethoxy—3-(3-(pyrrolidinyl)propyl)quinazolin-4(3H)—one To a solution of ydroxy-3,5-dimethyl-phenyI)—5,7—dimethoxy— 3H—quinazolinone (0.70 g, 2.14 mmol) in ous THF (50 mL) were added triphenyl phosphine (1.69 g, 6.43 mmol), 3-bromopropanol (0.60 g, 4.34 mmol) and N,N—diisopropylethyl amine (0.42 g, 3.22 mmol). To this stirred solution was added diethyl azodicarboxylate (1.13 g, 6.43 mmol). The reaction e was stirred at room temperature for 48 hours under nitrogen. Ethyl acetate (400 mL) was added; the organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous NagSO4. Solvent was removed under reduced pressure. The crude material was purified by the Simpliflash system (5:95 ethyl acetatezhexane as eluent) to give 2-[4-(3—bromo—propoxy)-3,5-dimethyl- phenyl]—3-(3-bromo-propyl)—5,7—dimethoxy—3H—quinazolinone as a white solid.

Yield: 0.765 g (63%).

To a solution of 2-[4-(3—bromo—propoxy)-3,5—dimethyl-phenyl](3— propyl)~5,7—dimethoxy-3H—quinazolinone (0.76 g, 1.35 mmol) in DMF (10 mL) were added pyrrolidine (0.77 g, 10.77 mmdl). The reaction mixture was stirred at room temperature for 16 hours. Then, water was added and product was extracted with ethyl e (2XZ00 mL). The combined organic layer was washed with water, then brine, and dried over NaZSO4. Solvent was evaporated to give the title compound as a white solid. Yield: 0.12 g (16%). MP 109-111°C. 1H NMR (400 MHz, CDCI3): 5 8.16 (s, 2H), 6.93 (cl, J = 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.71 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.87 (t, J = 6.0 Hz, 2H), 2.75 (m, 4H), 2.60 (m, 8H), 2.37 (s, 6H), 2.16 (m, 2H), 2.05 (m, 2H), 1.82 (m, 8H). MS (ES) m/z: 549.75 (M+1). Analysis ated for C32H44N4O4-05H20 (FW 557.73), %: C, 68.91; H, 8.13; N, 10.05. Found, %: C, 68.71; H, 8.56; N, 9.74.

Example 70. Preparation of 2—(4—Acetylpiperazinyl)ethoxy)-3,5— dimethylphenyl)—5,7-dimethoxyquinazolin-4(3H)—one OWN/W "mi "*5 /O O To a suspension of 2-[4-(2—bromoethoxy)—3,5-dimethylphenyl]-5,7- dimethoxy-3H—quinazolin—4—one (0.35 g, 0.81 mmol) in anhydrous DMF (9 mL) was added 1—acetylpyperazine (0.31 g, 2.42 mmol) and the reaction mixture was d at room temperature under nitrogen for 32 hours. Solvent was removed under reduced pressure and water (50 mL) was added. The separated solid was filtered, washed with water and ether, and dried under vacuum, to give the title nd as a white solid. Yield: 0.28 g (72%). MP 213-214°C. 1H NMR (400 MHz, CDCl3): 5 9.87 (br s, 1H), 7.74 (s, 2H), 6.83 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 3.97 (s, 3H), 3.95 (t, J = 5.0 Hz, 2H), 3.93 (s, 3H), 3.59 (t, J = 5.0 Hz, 2H), 3.53 (t, J = 5.0 Hz, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.52 (t, J = 5.0 Hz, 2H), 2.57 (t, J = 5.0 Hz, 2H), 2.39 (s, 6H), 2.11 (s, 3H). MS (ES') m/z 479.55 (100%, M-1).

Example 71. Preparation of 2—(4-(2—(1H-imidazoly|)ethoxy)—3,5- dimethylphenyi)—5,7-dimethoxyquinazolin-4(3H)—one To a solution of 2-[4-(2—bromoethoxy)—3,5-dimethylphenyl]-5,7— dimethoxy-3H—quinazolinone (0.12 g, 0.27 mmol) in e (5 mL) was added imidazole (0.18 g, 2.70 mmol) and 032C03 (0.26 g, 0.80 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure, and the residue was purified by column chromatography a gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give the title nd as a white solid. Yield: 0.04 g (35%). MP 218—219°C. 1H NMR (400 MHz, DMSO-de): 611.80 (br s, 1H), 7.83 (s, 2H), 7.72 (s, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.36 (t, J = 4.8 Hz, 2H), 4.02 (t, J = 4.8 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.06 (s, 6H). MS (ES) m/z: 419.57 (M—1).

Example 72. Preparation of 2-(3,5—DimethyI—4—(2—(pyrrolidiny|)ethoxy)phenyI) methoxyquinazoiin-4(3H)—one /o N\ {0315] To a stirred solution of 2-amino—4-methoxy—benzoic acid (3.00 g, 17.9 mmol) in THF (90 mL), EDCI (7.89 g, 41.1 mmol) and HOBt (7.95 g, 51.9 mmol) were added and stirred at room temperature for 30 minutes. Then, N- methylmorpholine (6.15 g, 60.0 mmol) and s 50% (v/v) NH4OH (12 mL, 171.4 mmol) were added. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (4X100 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous sodium sulfate. t was evaporated to give 2-aminomethoxy-benzamide as an off-white solid.

Yield: 1.80 g, (60%).

To a solution of 2-amino-4—methoxy-benzamide (1.00 g, 6.01 mmol) and 4-(2—hydroxy—ethoxy)-3,5-dimethyl-benzaldehyde (1.28 g, 6.59 mmol) in MN— dimethylacetamide (15 mL) were added NaH803 (58.5 wt%, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was stirred at 115 °C for 16 hours, and cooled to room ature. Solvent was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 hour, filtered, and dried under vacuum, to give 2—[4—(2—hydroxy-ethoxy)—3,5— dimethyI—phenyl]methoxy-3H—quinazolinone as an off-white solid. Yield: 1.20 g (58%).

To a solution of 2-[4-(2—hydroxy-ethoxy)—3,5—dimethyI-phenyl]-7— methoxy—3H—quinazolin—4—one (1.20 g, 3.52 mmol) in anhydrous DMF (15 mL) were added triphenylphosphine (1.00 g, 3.80 mmol) and carbontetrabromide (1.27 g, 3.80 mmol). The reaction mixture was stirred at room temperature for 16 hours.

DMF was removed under reduced pressure. The residue was purified by column tography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give —bromo-ethoxy)-3,5-dimethyl-phenyl]methoxy3H— quinazolin-4—one as an off-white solid. Yield: 0.37 g (26%).

To a solution of 2-[4—(2-bromo-ethoxy)—3,5-dimethyl—phenyl]—7- methoxy-3H—quinazolinone (0.30 g, 0.74 mmol) in DMF (5 mL) was added pyrrolidine (0.31 g, 4.36 mmol) and the reaction mixture was stirred at room ature for 15 hours. DMF was removed under reduced pressure, and the residue was purified by column tography (silica gel 0 mesh; 5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.13 g (44%). MP 218-220°C. 1H NMR (400 MHz, DMSO-de): 612.13 (br s, 1H), 8.03 (d, J = 8.98 Hz, 1H), 7.90 (s, 2H), 7.16 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.9 and 2.7 Hz, 1H), 3.92—3.89 (m, 5H), 2.83 (t, J = 5.8 Hz, 2H), 2.54- 2.50 (m, 4H), 2.31 (s, 6H), 1.73 (m, 4H). MS (ES+) m/z: 394.62(M+1).

Example 73. Preparation of 2-(3,5-Dimethyl(2-(4-methylpiperazin~1~ y|)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)—one /0 N\ K/l‘k To a solution of 2~[4—(2~bromo-ethoxy)—3,5-dimethyl-phenyl]-5,7- dimethoxy-3H—quinazolin-4—one (0.17 g, 0.39 mmol) in methylformamide (0.5 mL) was added N—methylpiperazine (0.44 mL, 3.92 mmol) and the reaction mixture was stirred at room temperature for 15 hours. N, N—dimethylformamide was d under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give the title nd as a white solid. Yield: 60 mg (33.8%). MP 180- 182°C. 1H NMR (400 MHz, DMSO-de): 611.76(s, 1H), 7.89 (s, 2H), 6.73 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.88 (m, 5H), 3.84 (s, 3H), 2.68 (t, J = 5.6 Hz, 2H), 2.50 (br s, 4H), 2.32 (br s, 4H), 2.30 (s, 6H), 2.15 (s, 3H). MS (ES+) m/z: 453.21 (M+1).

Example 74. Preparation of 2—(3,5-Dimethyl(2—(piperidinyl)ethoxy)phenyl)— ,7-dimethoxyquinazolin—4(3H)-—one /0 N\ To a solution of 2—[4—(2-bromo-ethoxy)-3,5-dimethyl—phenyl]—5,7- dimethoxy-3H—quinazolinone (0.34 g, 0.78 mmol) in DMF (10 mL) was added piperidine (0.27 g, 3.14 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, water was added and the product was ted with ethyl acetate (2X200 mL). The combined organic layer was washed with water, then brine, and dried over anhydrous Na2804. Solvent was evaporated to give the title compound as a white solid. Yield: 0.33 g (96%). 1H NMR (400 MHz, DMSO—d6)2811.80(br s, 1H), 7.87 (s, 2H), 6.72 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 3.86 (m, 6H), 3.82 (s, 2H), 2.63 (t, J = 5.6 Hz, 2H), 2.42 (m, 4H), 2.28 (s, 6H), 1.50 (m, 4H), 1.37 (m, 2H). MS (ES) m/z 438.63 (M+1).

Example 75. Preparation of 5,7-Dimethoxy(3-methyl—4-(2—(pyrrolidin yl)ethoxy)phenyl)quinazolin-4(3H)-one /o N\ /0 o To a solution of 4-hydroxy—3-methylbenzaldehyde (1.10 g, 8.08 mmol) in anhydrous DMF (12 mL) was added K2C03 (2.23 g, 16.16 mmol) and ethylene carbonate (1.42 g, 16.16 mmol) at room temperature. The resulting reddish-orange suspension was stirred at 110 °C for 6 hours under nitrogen. DMF was removed and the e was d with water (50 mL) and dichloromethane (50 mL). The organic phase was separated, and the s phase was extracted with romethane (2XZ0 mL). The ed organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 4-(2-hydroxy—ethoxy) methylbenzaldehyde as a brown oil. Yield: 1.46 g (100 %).

To a solution of 4-(2~hydroxy—ethoxy)—3-methylbenzaldehyde (1.46 g, 8.08 mmol) and o-4,6—dimethoxybenzamide (1.58 g, 8.08 mmol) in MN- dimethylacetamide (20 mL) were added NaH803 (58.5 wt%, 2.20 g, 12.12 mmol) and p—toluenesulfonic acid monohydrate (0.38 g, 2.02 mmol). The reaction mixture was stirred at 110 °C for 16 hours, then cooled to room temperature. N,N- dimethylacetamide was removed under reduced pressure. The residue was triturated with water (50 mL). The resulting slurry was filtered and solid was washed with water, ether, and hexanes to obtain 2—[4—(2-hydroxy—ethoxy)—3— methyl—phenyl]—5,7-dimethoxy—3H—quinazolinone as a beige solid. Yield: 2.75 g (95%).

Tetrabromomethane (3.26 g, 9.82 mmol) was added to a solution of triphenylphosphine (2.58 g, 9.82 mmol) in anhydrous DMF (20 mL) at 0 °C. A solution of 2-[4—(2-hydroxy—ethoxy)—3-methyl-phenyl]-5,7—dimethoxy—3H—quinazolin— 4-one (1.75 g, 4.91 mmol) in DMF (7 mL) was then added dropwise and stirred the reaction mixture at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with dichloromethane (4XZ5 mL). The combined organic phase was washed with brine and dried over ous magnesium e. The solvent was d and the solid was ated with ether. The resulting slurry was filtered and washed with ether several times (to remove the triphenylphosphine oxide) and finally with a solution of dichloromethane—ether (1:1) to obtain 2—[4~(2—bromo- ethoxy)—3-methyl—phenyl]-5,7-dimethoxy—3H—quinazolin—4-one as an off-white solid.

Yield: 0.70 g (34%).

To a suspension of 2-[4-(2—bromo—ethoxy)—3-methyl—phenyl]-5,7- dimethoxy-3H—quinazolin—4—one (0.70 g, 1.67 mmol) in anhydrous DMF (9 mL) was added pyrrolidine (0.55 mL, 6.68 mmol) and the reaction e was stirred at room temperature under nitrogen for 20 hours. Solvent was removed under reduced pressure and the residue was ed by column chromatography (silica gel 230-400 mesh; 9% methanol in dichloromethane as ) to give the title compound as an off-white solid. Yield: 0.62 g (90.6%). MP 230-231°C. 1H NMR (400 MHz, CDCl3): 8 9.96 (br s, 1H), .89 (m, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 2.98 (t, J = 6.0 Hz, 2H), 2.69 (br s, 4H), 2.32 (s, 3H), 1.84—1.81 (m, 4H). MS (ES') m/z 408.13 (M-1, 100%), MS (ES+) m/z 410.14 (M+1, 75%).

Example 76. Preparation of 3-(2-(4—(5,7~Dimethoxyoxo—3,4—dihydroquinazolin— 2~yl)-2,6-dimethylphenoxy)ethyl)—1-isopropylimidazolidine-2,4-dione OWN/("1% /O\ To a solution of 1-isopropyl—imidazolidine-2,4—dione (0.10 g, 0.70 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineral oil, 31 mg, 0.77 mmol) and the on mixture was stirred for 10 s. Then, 2-[4-(2-bromo-ethoxy)—3,5-dimethyl-phenyl]-5,7—dimethoxy-3H— quinazolin-4—one (0.32 g, 0.73 mmol) was added. The reaction mixture was d at 55 °C for 16 hours, then poured into water (100 mL). The solid was filtered and dried. The crude nd was purified by column chromatography (silica gel 230-400 mesh; eluting with 2:1 ethyl acetate and dichloromethane) to give the title compound as a white solid. Yield: 0.09 g (26.0 %). MP 219—221°C. 1H NMR (400 MHz, DMSO): 6 9.64 (s, 1H), 7.69 (s, 2H), 6.82 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.42 (m, 1H), 4.02 (m, 2H), 3.98 (m, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 2H), 2.32 (s, 6H) 1.22 (d, J = 6.4 Hz, 6H). MS (ES+) m/z: 495.16 (M+1).

Example 77. Preparation of —Dimethyl(3-(pyrrolidinyl)propoxy)phenyl)- ,7-dimethoxyquinazolin-4(3H)—one /omN\ /o o To a solution of 4—hydroxy-3, 5—dimethyl benzaldehyde (5.0 g, 33.29 mmol) in DMF (30 mL) were added 3-bromo propan—1-ol (5.56 g, 39.95 mmol) and Cs2C03 (16.24 g, 50.0 mmol). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the products were extracted with ethyl acetate (2X250 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2804. Removal of solvent gave 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 5.38 g (77%).

To a solution of 2-amino-4, 6—dimethoxy—benzamide (1.3 g, 6.63 mmol) and 4-(3~hydroxypropoxy)-3,5-dimethyl benzaldehyde (1.38 g, 6.63 mmol) in N,N-dimethyl acetamide (10 mL), NaH803 (1.30 g, 7.3 mmol), and p-TSA (252 mg, 1.32 mmol) were added and the reaction mixture was heated at 115 °C for 26 hours, then cooled to room temperature. The solvent was removed under reduced pressure. Then, water (100 mL) was added and d for 1 hour at room temperature. The ted solids were filtered and dried. The solids were again washed with l ether to give crude product 2-[4-(3-hydroxy-propoxy)—3,5- dimethyl—phenyl]—5,7-dimethoxy-3H-quinazolin—4-one as an off—white solid. Yield: 1.69 g (66%).

To a solution of 2-[4-(3—hydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7- dimethoxy-3H-quinazolinone (1.39 g, 3.62 mmol) in DMF (15 mL) were added PPh3 (1.04 g, 3.98 mmol) and CBr4 (1.32 g, 3.98 mmol).The reaction mixture was stirred at room temperature for 16 hours. Then, solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solids were dried and ed by the Simpliflash system, using 2% methanol in CH2CI2, to give 2-[4-(3-bromo-propoxy)—3,5-dimethyl-phenyl]-5,7-dimethoxy-3H- quinazolinone as a white solid. Yield: 940 mg (58%).

To a solution of 2-[4—(3-bromo-propoxy)—3, 5—dimethyl-phenyl]—5,7- dimethoxy-3H-quinazolin-4—one (340 mg, 0.76 mmol) in DMF (10 mL) was added pyrrolidine (433 mg, 6.08 mmol). Then, the on mixture was stirred at room temperature for 16 hours. Then, water was added and the solids were filtered. The solids were wshed with water and dried to give the title compound as a white solid. Yield: 307 mg (92%). 1H NMR (400 MHz, DMSO-de): 8 11.80 (s, 1H), 7.87 (s, 2H), 6.71 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 3.86 (s, 3H), 3.82 (m, 5H), 2.59(t, J = 6.8 Hz, 2H), 2.42 (m, 4H), 2.26 (s, 6H), 1.89 (m, 2H), 1.67 (m, 4H).

MS (ES) m/z: 438.16 (M+1). e 78. Preparation of 5,7-Dimethoxy—2—(4-(2-(pyrrolidin yl)ethoxy)phenyl)quinazolin-4(3H)—one /O O Carbon tetrabromide (0.26 g, 0.77 mmol) was added to a solution of triphenylphosphine (0.24 g, 0.92 mmol) in anhydrous DMF (5 mL) at 0 °C. A solution of 2-[4-(2ehydroxy—ethoxy)-phenyl]-5,7-dimethoxy-3H—quinazolin-4—one (0.21 g, 0.61 mmol) in DMF (2 mL) was then added dropwise and stirred at room temperature for 16 hours. Solvent was removed under reduced pressure and the residue was d with water (10 mL) and extracted with dichloromethane (4X10 mL). The combined organic phase was washed with brine and dried over ous magnesium sulfate. Solvent was removed and the residual solid was triturated with ether. The resulting slurry was filtered and washed with ether several times (to remove the triphenylphosphine oxide) and finally with a solution of dichloromethane—ether (1 :4) to obtain 2-[4-(2-bromo-ethoxy)-phenyl]-5,7- dimethoxy—3H—quinazolin—4-one as an off-white solid. Yield: 0.25 g (quantitative).

To a suspension of 2-[4-(2-bromo—ethoxy)-phenyl]—5,7-dimethoxy— 3H—quinazolinone (0.25 g, 0.61 mmol) in ous DMF (10 mL) was added pyrrolidine (0.20 mL, 2.45 mmol) and the reaction mixture was stirred at room temperature under nitrogen for about 20 hours. Solvent was removed under reduced pressure and the residual solid was ated with water. The resulting slurry was filtered and washed with ether and hexanes. The crude product was ed by column chromatography (silica gel 230-400 mesh; 10% methanol in romethane as eluent) to give the title compound as a white solid. Yield: 0.11 g (44%). MP 226-227°C. 1H NMR (400 MHz, CDCI3): 8 10.08 (br s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 1.95 Hz, 1H), 6.45 (d, J = 1.95 Hz, 1H), 4.21 (t, J = 5.6 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 2.97 (t, J = 5.6 Hz, 2H), 2.68 (br s, 4H), 1.84 (br s, 4H). MS (ES+): m/z 198.65 (100%), 396.10 (M+1, 70%).

Example 79. ation of 2-(3,5-Dimethyl—4—(3-(pyrrolidinyl)propyl)phenyl)- ,7-dimethoxyquinazolin-4(3H)-one To a solution of 2-amino—4,6-dimethoxy—benzamide (0.80 g, 4.00 mmol) and 4-(3-hydroxy—propyl)-3,5—dimethyl—benzaIdehyde (0.98 g, 5.1 mmol) in N,N—dimethylacetamide (15 mL) were added NaH803 (58.5 wt%, 0.80 g, 4.40 mmol) and p-TSA (0.155 g, 0.81 mmol) and the reaction mixture was heated at 115 °C for 16 hours, then cooled to room temperature. N,N~dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered and washed with water. The crude compound was purified by column chromatography (silica gel 230—400 mesh; 5% methanol in dichloromethane as eluent) to give 2-[4-(3-hydroxy-propyl)—3,5- dimethyl-phenyl]-5,7—dimethoxy-3H—quinazolinone as an ite solid. Yield: 1.10 g (73%).

To a on of 2—[4-(3-hydroxy-propyi)—3,5-dimethyl-phenyl]—5,7— dimethoxy-3H—quinazolin-4—one (1.00 g, 2.70 mmol) in anhydrous N,N- dimethylformamide (15 mL) were added triphenylphosphine (0.78 g, 3.00 mmol) and carbon romide (1.00 g, 3.00 mmol). The on mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in romethane as eluent) to give 2-[4-(3—bromo—propyl)-3,5- dimethyI-phenyl]-5,7-dimethoxy-3H—quinazolin-4—one as an off-white solid. Yield: 0.60 g (51%).

To a solution of 2-[4—(3-bromo—propyl)-3,5-dimethyl—phenyl]-5,7- dimethoxy-3H—quinazolin-4—one (0.40 g, 0.92 mmol) in methylformamide (10 mL) was added pyrrolidine (0.39 g, 5.52 mmol) and the reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 0 mesh; 5% methanol ammonia in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.27 g (69%). MP 194-196°C. 1H NMR (400 MHz, DMSO-de): 611.79 (br s, 1H), 7.81 (s, 2H), 6.72 (d, J = 2.3 Hz, 1H), 6.50 (d, J = 2.3 Hz, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 2.67-2.63 (m, 2H), 2.49-2.46 (m, 6H), 2.33 (s, 6H), 1.70-1.67 (m, 4H), 1.59—1.53 (m, 2H). MS (ES+) m/z: 422.17(M+1).

Example 80. Preparation of 2-(3,5—Dimethyl(4—(pyrrolidinyl)butoxy)phenyl)- ,7—dimethoxyquinazolin-4(3H)—one /o N\ To a solution of 4-hydroxy—3,5-dimethyl benzaldehyde (5.00 g, 33.3 mmol) in DMF (30 mL) were added 4—bromo-butan-1—ol (6.11 g, 39.9 mmol) and 032C03 (16.2 g, 50.0 mmol). The reaction mixture was stirred at room temperature for 48 hours, then water (100 mL) was added, and the products were ted with ethyl acetate (2XZ00 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous NaZSO4. Solvent was removed and the crude product was purified by the Simpliflash system, using 40% ethyl acetate in hexane as eluent, to give 4-(4- hydroxybutoxy)—3,5-dimethy| benzaldehyde as a colorless liquid. Yield: 0.66 g (7%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (497 mg, 2.53 mmol) and 4-(4-hydroxybutoxy)-3,5—dimethyl benzaldehyde (660 mg, 2.53 mmol) in N,N—dimethyl acetamide (10 mL), NaHSOs (58.5 wt%, 496 mg, 2.79 mmol) and p-TSA (96 mg, 0.50 mmol) were added and the reaction mixture was heated at 115 °C for 16 hours and then cooled to room temperature. The solvent was removed under reduced pressure. Water (100 mL) was added and d for 1 hour at room temperature. The solid separated was filtered and dried. The solid was further washed with diethyl ether to give product 4-hydroxy-butoxy)—3,5- dimethyl-phenyl]—5,7-dimethoxy-3H—quinazolinone as a white solid. Yield: 1.69 g (82%).

To a solution of 2-[4~(4-hydroxy-butoxy)-3,5—dimethyl—phenyl]—5,7- oxy-3H—quinazolin-4—one (675 mg, 1.69 mmol) in DMF (10 mL) were added PPh3 (489 mg, 1.86 mmol) and CBr4 (619 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried and then purified by the Simpliflash system using 5% methanol in Cchlg as the eluent to give 2—[4-(4—bromo—butoxy)-3,5—dimethyl—phenyll-5,7- dimethoxy—3H—quinazolin-4—one as a white solid. Yield: 494 mg (63%).

To a solution of 2-[4—(4-bromo-butoxy)—3,5-dimethyl-phenyl]—5,7- dimethoxy-3H—quinazolinone (494 mg, 1.07 mmol) in DMF (10 mL) was added pyrrolidine (609 mg, 8.57 mmol). The reaction e was stirred at room temperature for 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (2XZ00 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2804. Solvent was evaporated to give the title compound as a white solid. Yield: 278 mg ( 57%). MP 180-181°C. 1H NMR (400 MHz, CDCI3): 8 7.68 (s, 2H), 6.83 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.83 (t, J = 6.4 Hz, 2H), 2.56 (m, 6H), 2.36 (s, 6H), 1.88 (m, 2H), 1.79 (m, 6H). MS (ES) m/z: 452.21 (M+1). e 81. Preparation of 2—(3,5-Dimethyl—4-(2-(pyrrolidinyl)ethoxy)phenyl)—8— methoxyquinazolin-4(3H)—one EOE fiwfiN\NH To a solution of 2-aminomethoxy benzoic acid (5.00 g, 29.9 mmol) in THF (50 mL) were added EDCI (6.88 g, 35.9 mmol), HOBt (4.85 g, 35.9 mmol), N-methylmorpholine (3.60 g, 35.9 mmol), and aqueous a (50% WV, mL). Then, the reaction mixture was stirred at room ature for 48 hours.

Then, water was added and the product was ted with ethyl acetate (2XZ50 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous NaZSO4. Removal of solvent gave product 2-amino—3—methoxy- ide as a light orange solid. Yield: 1.70 g (34%).

To a solution of 2—amino-3—methoxy—benzamide (700 mg, 4.22 mmol) and 4-(2-hydroxyethoxy)—3,5-dimethyl benzaldehyde (823 mg, 4.22 mmol) in N,N-dimethyl acetamide (10 mL) were added NaH803 (58.5 wt%, 841 mg, 4.64 mmol) and p-TSA (160 mg, 0.84 mmol). The reaction mixture was heated at 115 °C for 16 hours, then cooled to room temperature. t was removed under reduced pressure. Water (100 mL) was added and stirred for 1 hour at room temperature. The solid ted was filtered and dried. The solid was r washed with diethyl ether to give crude t 2-[4—(2-hydroxy-ethoxy)-3,5- dimethyl—phenyI]-8—methoxy-3H—quinazolin-4—one as an off-white solid. Yield: 1.2 g (84%).

To a on of 2-[4-(2-hydroxy-ethoxy)—3,5-dimethyl-phenyl]—8- methoxy-3H—quinazolin-4—one (1.20 g, 3.53 mmol) in DMF (10 mL) were added PPh3 (1.02 g, 3.88 mmol) and CBr4 (1.29 g, 3.88 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried under vacuum and purified by the Simpliflash system, using 2% methanol in CHZCIZ as eluent, to give 2-[4-(2-bromo-ethoxy)—3,5-dimethyl—phenyl]—8-methoxy- 3H-quinazolinone as a white solid. Yield: 0.547 g (38%).

To a solution of 2~[4-(2-bromo-ethoxy)-3,5-dimethyI-phenyl]—8- methoxy—3H—quinazolin—4—one (537 mg, 1.33 mmol) in DMF (10 mL) was added a pyrrolidine (758 mg, 10.66 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the solid seperated was filtered and dried under vacuum. The solid was triturated with ether and dried to give the title compound as a white solid. Yield: 232 mg (44%). MP 231—232°C. 1H NMR (400 MHz,CDCl3):810.30(s, 1H), 7.90 (dd, J = 8.0 Hz, 1H), 7.806 (br s, 2H), 7.42 (t, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.04(s, 3H), 3.95 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.65 (m, 4H), 2.40 (s, 6H), 1.84 (m, 4H). MS (ES) m/z: 394.15 (M+1).

Example 82'. Preparation of 3—(2-(4-(5,7-Dimethoxy—4-oxo-3,4-dihydroquinazolin- 2—yl)—2,6-dimethylphenoxy)ethyI)—5—phenylimidazolidine—2,4—dione /0 N\ O//\'\NH To a suspension of 2-[4—(2-hydroxy—ethoxy)—3,5—dimethyl-phenyl]- ,7-dimethoxy-3H—quinazolin—4-one (0.50 g, 1.35 mmol) in THF (20 mL), were added 5-phenyl-imidazolidine-2,4-dione (0.24 g, 1.35 mmol) and triphenyl ine (0.35 g, 1.35 mmol), then diethyl arboxylate (0.43 mL, 2.70 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Solvent was evaporated in vacuo and the residue was washed with dichloromethane and ether. The residue was ved in acetic acid and purified by preparative HPLC. The compound was further washed with dichloromethane and ether (1:1, 20 mL) to obtain the title compound as a white solid. Yield: 0.07 g (10%). MP 219.6-221.4°C. 1H NMR (400 MHz, DMSO-ds): 6 8.81 (s, 1H), 7.86 (s, 2H), 7.37 (m, 5H), 6.71 (s, 1H), 6.48 (s, 1H), 3.94 (m, 4H), 3.86 (s, 3H), 3.82 (s, 3H), 2.18 (s, 6H). MS (ES) m/z: 529.29 (M++1). e 83. Preparation of 3-(4-(5,7-Dimethoxyoxo—3,4-dihydroquinazolin—2- yl)benzyl)imidazolidine~2,4—dione Hydantoin (0.80 g, 8.00 mmol) was dissolved in DMF (10 mL) and cooled to 0 °C. Sodium hydride (60% in mineral oil, 88 mg, 2.20 mmol) was added. The mixture was stirred at room temperature for 3 hours. 4- (Bromomethyl)benzaldehyde (0.40 g, 2.00 mmol) was added. The mixture was stirred at room temperature for 2.5 days. Saturated aqueous NH4Cl (1 mL) was added. The mixture was concentrated to dryness. Water (10 mL) was added, extracted with dichloromethane, and the organic phase was dried over anhydrous Na2SO4. Solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH20I2 as eluent) to give 4—(2,5-dioxo-imidazolidinylmethyl)-benzaldehyde as a white solid. Yield: 0.28 g (64%).

To a solution of 2-amino-4,6-dimethoxy—benzamide (0.19 g, 0.98 mmol) in N,N-dimethylacetamide (4 mL) were added 4-(2,5-dioxo-imidazolidin ylmethyl)—benzaldehyde (0.19 g, 0.89 mmol), sodium en sulfite (58.5 wt%, 0.24 g, 1.30 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) and the reaction mixture was stirred at 115 °C for 17 hours under nitrogen, then cooled to room temperature. The precipitate was filtered, washed with methanol, water, then methanol, and dried in air. The solid was suspended in hot DMSO (approximately 3 mL); saturated aqueous NaH003 ximately 3 mL) and water were added. The solid was filtered, washed with water, then methanol, and air dried to give the title compound as a light yellow solid. Yield: 0.16 g (46%). MP 800. 1H NMR (400 MHz, DMSO-ds):812.05(s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 4.61 (s, 2H), 4.02 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ES+) m/z: 395.09 (M+1).

Example 84. Preparation of 2—(3,5—Dimethyl—4-(2—(pyrrolidin—1~yl)ethoxy)phenyI) methoxyquinazolin-4(3H)-one To a suspension of 2-aminomethoxy—benzoic acid (5.00 g, 30.0 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3—ethylcarbodiimide hydrochloride (7.50 g, 39.0 mmol), 1-hydroxybenzotriazole (4.50 g, 33.0 mmol) and 4-methylmorpholine (3.6 mL, 33.0 mmol) and the reaction mixture was stirred at room temperature for 1 hours. Then, 50% aqueous NH3 (8 mL, 105.0 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours.

Water (100 mL) was added and the product was extracted with ethyl acetate.

Solvent was evaporated in vacuo and the residue was washed with ether to give 2-amino-5—methoxy-benzamide as a white solid. Yield: 2.62 g (53%).

To a stirred on of 2-aminomethoxy-benzamide (2.62 g, .80 mmol) and 4-(2—hydroxy—ethoxy)—3,5—dimethyl—benxaldehyde (3.23 g, 16.60 mmol) in N,N-dimethyl acetamide (20 mL), were added sodium hydrogen sulfite (58.5 wt%, 3.44 g, 19.00 mmol) and p-toluenesulfonic acid monohydrate (0.60 g, 3.20 mmol) and the reaction e was stirred at 115 °C for 16 hours. t was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was triturated with ether to give 2—[4-(2-hydroxy-ethoxy)—3,5- dimethyl-phenyl]—6—methoxy-3H—quinazolin-4—one as a white solid. Yield: 3.56 g (66%).

To a suspension of 2-[4-(2-hydroxy-ethoxy)—3,5-dimethyl-phenyl]—6- methoxy-3H—quinazolinone (1.50 g, 4.41 mmol) in N,N-dimethylformamide (15 mL), carbon tetrabromide (1.60 g, 4.85 mmol), and triphenylphosphine (1.30 g, 4.85 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the product was purified by the Simpliflash system, using 1-2% methanol in CH20|2 as eluent, to give 2—[4- (2—bromo—ethoxy)—3,5-dimethyl-phenyl]—6-methoxy—3H—quinazolin-4—one as a white solid. Yield: 1.77 g (quantitative).

To a suspension of 2-[4—(2-bromo—ethoxy)—3,5-dimethyI-phenyl]~6— methoxy—3H—quinazolinone (1.94 g, 4.80 mmol) in N,N-dimethylformamide (20 mL), pyrrolidine (4 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. t was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was washed with ether to give the title nd as a light brown solid. Yield: 0.30 g (16%). MP 203.1°C. 1H NMR (400 MHz, CDCI3): 6 7.73 (m, 4H), 7.39 (m, 1H), 3.98 (t, J = 6.0 Hz, 3H), 3.94 (s, 3H), 2.97 (t, J = 6.0 Hz, 2H), 2.69 (br s, 4H), 2.41 (s, 6H), 1.86 (br s, 4H). MS (ES) m/z: 394.21 .

Example 85. Preparation of 2-(3,5—Dimethyl—4-(2-(pyrrolidinyl)ethoxy)phenyl)- ,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one /o N N /o o To a solution of 2-aminc-4,6-dimethoxy—nicotinamide (0.60 g, 3.00 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.59 g, 3.00 mmol) in N,N—dimethylacetamide (8 mL) was added NaH803 (58.5 wt%, 0.59 g, 3.30 mmol) and p—TSA (0.22 g, 1.20 mmol). The reaction mixture was heated to 145- 148 °C for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced re, the residue was diluted with sodium bicarbonate solution (50 mL), and the solid separated was filtered and dried under vacuum. The crude compound was purified by column chromatography (silica gel 230—400 mesh; 5% methanol in dichloromethane as ) to give 2-[4-(2— hydroxy-ethoxy)—3,5-dimethyl-phenyi]—5,7—dimethoxy—3H—pyrido[2,3-d]pyrimidin one as a white solid. Yield: 0.50 g (49%).

To a solution of 2-[4-(2-hydroxy-ethoxy)—3,5-dimethyI-phenyI]-5,7- dimethoxy—3H—pyrido[2,3—d]pyrimidinone ( 0.50 g, 1.34 mmol) in anhydrous DMF (6 mL) was added carbon tetrabromide (0.53 g, 1.61 mmol) and triphenylphosphine (0.42 g, 1.61 mmol). The on mixture was stirred at 25 °C for 16 hours. DMF was removed under vacuum and dichloromethane (200 mL) was added. The organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was removed and the residue was washed with ether (100 mL) to give 2-[4—(2-bromo-ethoxy)-3,5— dimethyl-phenyI]-5,7-dimethoxy-3H—pyrido[2,3—d]pyrimidin—4-one as a white solid.

Yield: 0.23 g (40%).

A solution of 2-[4-(2-bromo—ethoxy)-3,5-dimethyl-phenyI]-5,7- dimethoxy-3H—pyrido[2,3—d]pyrimidin—4—one (0.20 g, 0.46 mmol) in pyrrolidine (2 mL) was stirred at room temperature for 3 hours. The excess pyrrolidine was removed under reduced pressure, and the residue was purified by column chromatography a gel 230-400 mesh; eluting with 2% 2.0 M ammonia in methanol solution and dichloromethane) to give the title compound as a white solid. Yield: 0.17 g (87%). MP 0°C. 1H NMR (400 MHz, CDCI3)I 610.06 (s, 1H), 7.83 (s, 2H), 6.22 (s, 1H), 4.12 (s, 3H), 4.00 (s, 3H), 3.95 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.64 (m, 4H), 2.37 (s, 6H), 1.80 (m, 4H). MS (ES+) m/z: 425.19 (M+1). e 86. Preparation of 2—(3,5-Dimethyl-4—(2-(pyrrolidin—1—yl)ethoxy)phenyl)—7- fluoro(pyrrolidiny|)quinazo|in-4(3H)~one A mixture of 2-amino-4,6—difluoro-benzamide (0.96 g, 5.60 mmol), 4- (2-hydroxy-ethoxy)—3,5—dimethyl-benzaldehyde (1.09 g, 5.60 mmol), NaH803 (58.5wt%, 1.00 g, 5.60 mmol) and p—toluenesulfonic acid drate (1.44 g, 7.06 mmol) in N,N—dlmethylacetamide (25 mL) was stirred at 120 °C for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure.

The residue was diluted with water (100 mL). The solid separated was filtered and washed with water and dried under vacuum to give fluoro[4—(2-hydroxy- ethoxy)-3,5—dimethyl-phenyl]-3H—quinazolin—4—one as a white solid. Yield: 1.559 (79%).

A mixture of fluoro[4-(2-hydroxy-ethoxy)-3,5-dimethyl— phenyl]~3H—quinazolinone (1.54 g, 4.44 mmol), PPh3 (1.52 g, 5.78 mmol), and CBr4 (1.92 g, 5.78 mmol) in anhydrous DMF (30 mL) was stirred at room temperature for 36 hours. DMF was evaporated under vacuum, water (100 mL) was added, and stirred for 30 minutes. The solid separated was filtered, washed with water, then ether, and dried under vacuum to give 2-[4-(2-bromo—ethoxy)-3,5— dlmethyl-phenyl]-5,7—dlfluoro-3H—quinazolinone as pale yellow solid. Yield: 1.38 g (crude). This t was used in the next step without further purification.

A solution of 2-[4—(2-bromo-ethoxy)—3,5-dimethyl-phenyl]-5,7- difluoro-3H—quinazolinone (1.38 g, crude) and pyrrolidine (10 mL) was stirred at room ature for 16 hours. Excess pyrrolidine was evaporated, the residue was purified by column chromatography (silica gel 230—400 mesh; 30-50% ethyl acetate in hexanes as eluent). The compound was further purified by preparative HPLC to give the title compound as a white solid. Yield: 260 mg (13% for two steps). MP 206.6-206.8°C. 1H NMR (400 MHz, e): 8 11.85 (s, 1H), 6.63 (d, J = 8 Hz, 1H), 6.51 (d, J =12 Hz, 1H), 3.90 (t, J = 4 Hz, 2H), 2.83 (t, J = 4 Hz, 2H), 2.50 (s, 6H), 2.30 (s, 4H), 1.89 (s, 4H), 1.70 (s, 4H).

Example 87. Preparation of 5-Chloro(3,5-dimethyl(2-(pyrrolidin—1— yl)ethoxy)phenyl)quinazolin-4(3H)-one (1 \ .NH To a solution of 2-aminochlorobenzoic acid (2.00 g, 11.65 mmol) in anhydrous THF (20 mL) were added 4-methylmorpholine (1.40 mL, 12.82 mmol), HOBT (1.73 g, 12.82 mmol), and EDCI (2.45 g, 12.82 mmol); the reaction mixture was stirred at room temperature for 30 minutes. 50% (v/v) Ammonium hydroxide solution (10 mL, 132.0 mmol) was added and the mixture was d at room temperature for 23 hours. Solvent was evaporated to about 20 mL, poured into aqueous NaHC03 solution (200 mL) and extracted with ethyl acetate (7X100 mL). The organic phase was washed with water (3X100 mL), dried (N32804), filtered, and evaporated, to give 2—amino—6-chlorobenzamide as a white solid.

Yield: 1.65 g (83%). 4—(2—Hydroxyethoxy)—3,5-dimethylbenzaldehyde (0.70 g, 3.58 mmol), 2-amino—6-chlorobenzamide (0.60 g, 3.51 mmol), sodium bisulfite (0.71 g, 3.86 mmol) and p-toluenesulfonic acid drate (0.133 g, 0.699 mmol) in anhydrous N,N—dimethyl acetamide (14 mL) were heated at 120 °C under nitrogen for 23 hours. The solvent was evaporated and the white solid was triturated with water (50 mL), filtered, and washed with water (20 mL). The solid was dried in vacuo and ated with Eth (20 mL), filtered, and dried to give 5-chloro(4—(2— hydroxyethoxy)—3,5-dimethylphenyl)quinazolin-4(3H)—one as a white solid. Yield: 0.77 g, (64%).

To a solution of 5-chloro—2—(4-(2—hydroxyethoxy)—3,5- dimethylphenyl)quinazolin—4(3H)-one (0.40 g, 1.16 mmol) in anhydrous DMF (10 mL) was added carbon tetrabromide (0.42 g, 1.27 mmol) and nylphoshine (0.33 g, 1.27 mmol). The reaction mixture was stirred at room ature for 27 hours. Solvent was evaporated to dryness in vacuo and the residue triturated with EtZO (15 OAc (15 mL) to give 2—(4-(2-bromoethoxy)-3,5-dimethylphenyl)—5- quinazolin-4(3H)—one (0.42 g). It was used without further purification. The 1H NMR indicated a purity of about 45%.

To a solution of 2-(4—(2-bromoethoxy)-3,5-dimethylphenyl)—5- chloroquinazolin-4(3H)-one (0.40 g, crude) in anhydrous DMF (10 mL) was added pyrrolidine (0.36 mL, 4.35 mmol) and the reaction mixture was stirred at room temperature, under nitrogen, for 25 hours. t was evaporated to dryness in vacuo. The residue was triturated with water (50 mL), filtered, and the brown solid washed with 320 (20 mL). The crude material was purified by column chromatography a gel 230-400 mesh; 6% methanol in dichloromethane as the eluent) and then by reverse-phase HPLC (0.1% aqueous trifluoroacetic acid/acetonitrile as the eluent), to give a white solid. The solid was dissolved in CH2C|2 (20 mL)/MeOH (4.5 mL), washed with 1 M Na2C03 (4.5 mL) and the organic phase separated. The aqueous phase was extracted with CH2C|2 (4X20 mL). The ed organic phase was washed with water (10 mL), dried (Na2804), filtered, and evaporated to give the title compound as a white solid.

Yield: 0.091 g (21%, for two steps). MP 179-180°C. 1H NMR (400 MHz, DMSO~ d5): 8 12.30 (br s, 1H), 7.89 (s, 2H), 7.77-7.66 (m, 1H), 7.66-7.60 (m, 1H), 7.47 (d, J = 7.42 Hz, 1H), 3.89 (t, J = 5.85 Hz, 2H), 2.80 (t, J = 5.85 Hz, 2H), 2.53 (br s, 4H), 2.30 (s, 6H), 1.68 (br s, 4H). MS (ES+) m/z: 398.11 (100%), 400.13, 401.07.

Example 88. Preparation of 2-(4-(2-(Azepanyl)ethoxy)—3,5-dimethylphenyl)—5,7- dimethoxyquinazolin-4(3H)-one /o C I N\ /0 o To a suspension of 2-[4-(2-bromo-ethoxy)—3,5-dimethyl-phenyl]-5,7- dimethoxy-3H—quinazolinone (0.22 g, 0.50 mmol) in DMF (2 mL) was added hexamethyleneimine (azepane) (0.22 mL, 2.0 mmol) and the reaction e was stirred at room temperature for 17 hours. Saturated aqueous NaHC03 on (2 mL) was added and stirred for 2 hours. Water (10 mL) was added and stirred for r 0.5 hours. The solid was filtered, washed with water, and dried under vacuum to give the title compound as a white solid. Yield: 0.22 g (95%). MP 198- 199°C. 1H NMR (400 MHz, CD30D): 6 7.70 (s, 2H), 6.79 (s, 1H), 6.55 (s, 1H), 3.97 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.98 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 5.2 Hz, 4H), 2.37 (s, 6H), 1.72 (m, 4H), 1.66 (m, 4H). MS (ES+) m/z: 452.27 (M+1). is calculated for C26H33N304 (451.56), %: C 69.16, H 7.37, N 9.31.

Found, %: C 68.94, H 6.90, N 9.30.

Example 89. Preparation of 2-(3,5-Dimethyl—4-(2—(pyrrolidinyl)ethoxy)phenyl)- ,7—difluoroquinazolin-4(3H)-one Fmm Npromo F O To a solution of 2—amino-4,6—difluoro-benzamide (0.80 g, 4.60 mmol) and 3,5—dimethyl—4—(2-pyrrolidin-1—y|—ethoxy)—benzaldehyde (1.14 g, 4.60 mmol) in N,N-dimethylacetamide (60 mL) were added sodium hydrogen sulfite (58.5 wt%, 1.25 g, 6.9 mmol) and p~toluenesulfonic acid monohydrate (3.50 g, 18.4 mmol).

The reaction mixture was d at 145 °C for 16 hours under nitrogen atmosphere, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (50 mL) was added, followed by saturated aqueous sodium bicarbonate solution (15 mL). The mixture was extracted with CH2Cl2 (2X100 mL) and washed with water. The c phase was evaporated and the residue was washed with /ether (90:10, 100 mL). The solid was filtered and dried under vacuum to give the title nd as a brown solid. Yield: 1.48 g (80%). MP 234-235°C. 1H NMR (400 MHz, DMSO—ds): 5 12.36 (s, 1H), 7.90 (s, 1H), 7.32 (m, 2H), 3.91 (t, J = 4 Hz, 2H), 2.83 (t, J = 4 Hz, 2H), 2.55 (s, 4H), 2.31 (s, 6H), 1.70 (s, 4H).

Example 90. Preparation of 2—(4-(2-(Azetidin—1-y|)ethoxy)-3,5—dimethylphenyl)— ,7—dimethoxyquinazolin-4(3H)—one /o N\ /o o To a suspension of 2—[4-(2-bromoethoxy)—3,5-dimethyl~phenyl]—5,7- dimethoxy-BH—quinazolin—4-one (216 mg, 0.50 mmol) in DMF (5 mL) was added ine (154 mg, 2.70 mmol). The reaction mixture was stirred at room temperature for 2 days. The solid was collected by filtration, washed with methanol, ethyl acetate, and water, and dried under vacuum to give the title compound as a white solid. Yield: 58 mg (28%). MP 204—205°C. 1H NMR (400 MHz, DMSO—ds): 8 7.85 (s, 2H), 6.71 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 1H), 3.70 (t, J = 6.0 Hz, 2H), 3.18 (t, J = 6.8 Hz, 4H), 2.70 (t, J = 6.0 Hz, 2H), 2.26 (s, 6H), 1.97 (m, 2H). Ms (ES) m/z: 410.20 (M+1) (100%).

Example 91. Preparation of N—(1-(2—(4-(5,7-Dimethoxy—4-oxo-3,4- dihydroquinazolin-Z-yI)-2,6—dimethylphenoxy)ethyl)azetidin—3-yl)acetamide O\/\NinkO /OQ?"N\ To a solution of N-(1-benzhydryl-azetidin—3—y|)-acetamide (1.00 g, 3.57 mmol) in ethanol (20 mL) were added palladium ide on carbon (20 wt%, 0.20 g) and concentrated HCi (0.6 mL). The reaction mixture was hydrogenated at 50 psi at 40 °C for 2 hours. Then, the solid was filtered and washed with methanol (50 mL). The filtrate was collected; the solvent was evaporated to give N—azetidinyl-acetamide as a green gummy material. Yield: 0.40 g (crude). This product was used in next step without further cation.

To a suspension of N-azetidinyl—acetamide (0.30 g crude, 1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]—5,7-dimethoxy-3H— quinazolin-4~one (0.43 g, 1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was d at room temperature for 3 days under nitrogen. Solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered. The s phase was extracted with ethyl acetate (2X100 mL). The organic phase was dried over anhydrous NaZSO4. Solvent was evaporated, and crude compound was purified by the Simpliflash system (0—5% 7 N ammonia in methanol and CHch2 as eluent) to give the title compound as a white solid. Yield: 0.30 g (63%). MP 111.8—113.6°C. 1H NMR (400 MHz, CDCI3): 69.60 (br s, 1H), 7.69 (s, 2H), 6.82 (d, J = 2.34 Hz, 1H), 6.46 (d, J = 2.34 Hz, 1H), 6.10 (d, J = 7.81 Hz, 1H), 4.71 - 4.44 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.85 - 3.67 (m, 4H), 3.26 - 3.13 (m, 2H), 2.90 (t, J = 5.46 Hz, 2H), 2.36 (s, 6H), 2.01 (s, 3H). MS (ES+) m/z: 467.20 (M+1).

Example 92. Preparation of -Dimethyl—4-(2-(pyrrolidinyl)ethoxy)phenyl)- , 5,7-diisopropoxyquinazolin—4(3H)-one To a solution of 2—[4~(2-hydroxy-ethoxy)—3,5—dimethyl—phenyl]-5,7- diisopropoxy-3H—quinazolin—4-one (0.73 g, 1.70 mmol) in DMF (10 mL) were added PPh3 (0.49 g, 1.87 mmol) and 0&2; (0.62 g, 1.87 mmol).The reaction mixture was d at room temperature for 16 hours. Then, solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate.

The solid was dried and purified by the Simpliflash system (2% methanol in Cchlz as eluent) to give 2—[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7- diisopropoxy-3H—quinazolinone as a white solid. Yield: 0.39 g (47%).

To a solution of 2-[4—(2-bromo—ethoxy)—3,5-dimethyl-phenyl]—5,7— diisopropoxy-3H—quinazolin-4—one (0.39 g, 0.79 mmol) in DMF (10 mL) was added idine (0.45 g, 6.37 mmol). The on mixture was stirred at room temperature for 4 hours. Then, water was added and product was ted with ethyl acetate (2X200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2804. Solvent was evaporated to give the title compound as a white solid. Yield: 0.32 g (83%). MP 65—68°C. 1H NMR (400 MHz, CDClg): 5 9.05 (br s, 1H), 7.63 (s, 2H), 6.78 (s, 1H), 6.42 (s, 1H), 4.70 (m, 1H), 4.63 (m, 1H), 3.94 (m, 2H), 2.94 (m, 2H), 2.64 (br s, 4H), 2.38 (s, 6H), 1.84 (m, 4H), 1.46 (m, 3H), 1.42 (m, 3H). MS (ES) m/z: 480.29 (M+1).

Example 93. Preparation of ro(3,5—dlmethyI—4-(2—(pyrrolidin—1- yl)ethoxy)phenyl)quinazolin-4(3H)—one CI fiwfi (ElfinN\ To a solution of 2-amino—3—chloro—benzoic acid (2.57 g, 15.0 mmol) in THF (100 mL) were added EDCl (3.16 g, 16.5 mmol), HOBt (2.23 g, 16.5 mmol) and N-methylmorpholine (1.67 g, 16.5 mmol). The reaction mixture was stirred at room temperature for 20 s then 50% (v/v) aq. NH4OH solution (4.2 mL, 60.0 mmol) was added. The mixture was d for 20 hours at room temperature.

Solvent was evaporated and the residue was taken in ethyl acetate (200 mL).

Water (100 mL) was added. The organic phase was separated; the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated and dried under vacuum to give o— 3-chloro—benzamide as a white solid. Yield: 2.07 g (81%).

To a solution of 2-aminochloro-benzamide (0.85 g, 5.00 mmol) and 3,5—dimethyl(2—pyrrolidinyl-ethoxy)-benzaldehyde (1.23 g, 5.00 mmol) in N,N-dimethylacetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt%, 1.37 g, 7.50 mmol) and p-toluenesulfonic acid monohydrate (3.80 g, 20.0 mmol).

The on mixture was stirred at 140 °C for 16 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure.

Water (100 mL) was added, and the mixture was neutralized, to pH approximately 8 with 2 N aqueous NaOH solution. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was ed by the Simpliftash system (0-5% methanol in CH2C|2 and then 5% 7.0 M ammonia in methanol and CH2C|2 as eluent) to give the title compound as a brown solid. Yield: 0.49 g (25%). MP 216-217°C. 1H NMR (400 MHz, DMSO—ds): 8 8.07 (d, J = 7.81 Hz, 1H), .87 (m, 3H), 7.43 (t, J = 7.81 Hz, 1H), 3.89 (t, J = 5.85 Hz, 2H), 2.81 (t, J = 5.85 Hz, 2H), 2.53 (br s, 4H), 2.30 (s, 6H), 1.75 - 1.60 (m, 4H). MS (ES+) m/z 398.11 (100%), 400.13 (40%).

Example 94. Preparation of 2—(3,5-Dimethyl-4—(2-(pyrrolidinyl)ethoxy)phenyl)— ,7-dimethquuinazolin—4(3H)-one l hydrate (15.29 g, 92.42 mmol) was taken in water (335 mL).

Sodium sulfate (78.14 9, 550.13 mmol) was added at room temperature. Then, a suspension of hydroxylamine hydrochloride (18.35 9, 264.06 mmol), 3.5- dimethylaniline (10.0 g, 82.52 mmol) and concentrated hydrochloric acid (36.5%, mL) was added. The mixture was heated at 45 °C for 1.5 hours, then 75 °C for 1 hour. The reaction mixture was cooled to room temperature. The precipitated brown solid was filtered and washed with cold water (50 mL) and hexane (50 mL).

The crude compound was dried under vacuum to give N-(3,5-dimethyI-phenyl) yimino-acetamide as a brown solid. Yield: 13.7 g (86%). The crude nd was used in the next step t further purification.

N-(3,5-DimethyE—phenyl)hydroxyimino-acetamide (13.7 g 71.3 mmol) was added to concentrated sulfuric acid (70 mL) in a 250 mL flask. The reaction mixture was then heated at 80 °C for 30 minutes, then cooled to room temperature, and poured into ice-water (200 mL). The precipitated solid was filtered and washed with water (100 mL) and dried under vacuum to give 4,6- dimethyl—1H—indole-2,3—dione as an orange solid. Yield: 5.53 g (44%).

To a heated (70 °C bath temperature) deep red solution of 4,6- dimethyl—1H—indoIe—2,3-dione (1.00 g, 5.71 mmol) in 33% aqueous sodium hydroxide (35 mL) was added 35% hydrogen peroxide (3.33 g, 34.3 mmol) over a period of 5 minutes. The reaction mixture was heated for another 15 min, then cooled to room ature, and ice was added. The pH was adjusted to approximately 8 with concentrated HCI at 0 °C and acidified further to pH approximately 6 with glacial acetic acid. The solid precipitated was filtered, washed well with cold water, and dried under vacuum at 40 °C overnight to obtain 2-amino-4,6-dimethyl-benzoic acid as a pale brown solid. Yield: 0.35 g (37%).

To a solution of 2-amino-4, 6—dimethyl-benzoic acid (0.35 g, 2.08 mmol) in anhydrous THF (10 mL) was added EDCl (0.80 g, 4.17 mmol), HOBt (0.80 g, 5.22 mmol) and N—methyI-mopholine (0.7 mL, 6.24 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then ammonium hydroxide (50% v/v, 2.5 mL) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure.

Water (50 mL) was added, and the mixture was extracted with dichloromethane (2X100 mL). The ed organic phase was washed with water, and dried over anhydrous Na2804. Removal of the solvent gave the crude t. The crude product was purified by column tography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2—amino—4,6-dimethyI-benzamide.

Yield: 0.20 g (59%).

To a solution of 2-amino—4,6-dimethyl—benzamide (0.20 g, 1.22 mmol) and 3,5-dimethyI-4—(2-pyrrolidin—1—y|—ethoxy)—benzaldehyde (0.36 g, 1.46 mmol) in N,N-dimethy|acetamide (10 mL) was added NaH803 (58.5 wt%, 0.55 g, 3.05 mmol) and p—TSA (0.46 g, 2.44 mmol). The reaction mixture was heated to 110 °C for 2 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with sodium bicarbonate solution (50 mL), and the solid separated was filtered and dried under vacuum. The crude compound was purified by column chromatography a gel 230-400 mesh; 6% methanol in dichloromethane as eluent) to give the title und as a white solid. Yield: 0.145 g (30%). MP 181—182°C. 1H NMR (400 MHz, DMSO—de): 8 10.62 (s, 1H), 7.75 (s, 2H), 7.44 (s, 1H), 7.03 (s, 1H), 3.95 (t, J = 6.0 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.85 (s, 3H), 2.65 (s, 4H), 2.44 (s, 3H), 2.39 (s, 6H), 1.84 (s, 4H). MS (ES+) m/z: 392.13 (M+1).

Example 95. Preparation of 2-(2-(4-(6,8-Dimethoxy—1-oxo-1 ,2-dihydroisoquinolin- 3-yl)-2,6—dimethylphenoxy)ethyl)isoindoline-1,3-dione O O To a suspension of 3-[4-(2-hydroxy-ethoxy)-3,5—dimethyl-phenyl]- methoxy-2H-isoquinolinone (0.80 g, 2.16 mmol), isoindoIe-1,3-dione (0.35 g, 2.38 mmol), and triphenylphosphine (0.85 g, 3.25 mmol) in THF (30 mL), was added l azodicarboxylate (0.56 g, 3.25 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was washed with ether to give the title compound as an off-white solid. Yield: 1.11 g (crude). 1H NMR (400 MHz, : 6 8.34 (s, 1H), 7.89 (m, 2H), 7.77 (m, 2H), 7.21 (s, 2H), 6.49 (br s, 2H), 6.44 (s, 1H), 4.16 (m, 2H), 4.08 (m, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 2.25 (s, 6H). MS (ES) m/z: 499.06 (M+1) (100%).

Example 96. Preparation of 2-(3,5-Dimethyl(2-(pyrrolidin—1—yl)ethoxy)phenyl)- ,7-diisopropoxypyrido[2,3-d]pyrimidin—4(3H)—one YO N N \ \ To a suspension of 2—aminohydroxyoxo—1,6-dihydro—pyridine—3~ carboxylic acid methyl ester (7.0 g, 38.04 mmol), 2-iodopropane (14.22 g, 83.69 mmol), and K2C03 (11.56 g, 83.69 mmol) in DMF (200 mL), was heated at 60 °C for 48 hours, then cooled to the room temperature and filtered. Water (400 mL) was added to the filtrate and the product was extracted with ethyl acetate (3X200 mL). The combined organic layer was washed with water, then brine, dried over NaZSO4, and evaporated to give crude product. The crude product was purified by Simpliflash, using 10% ethyl acetate in hexane, to give 2-amino—4, opropoxy— nic acid methyl ester as a colorless oil. Yield: 1.30 g (13%). 1H NMR (400 MHz, DMSO-d6)15 6.91 (s, 2H), 5.57 (s, 1H), 5.19 (m, 1H), 4.59 (m, 1H), 3.66 (s, 3H), 1.23 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 1.2 Hz, 6H).

To the solution of o-4, 6~diisopropoxy~nicotinic acid methyl ester (1.6 g, 5.97 mmol) in methanol (9.0 mL) and water (1.0 mL), was added lithium hydroxide (750 mg, 17.91 mmol). The reaction mixture was heated to 50 °C for 8 hours. The solvent was removed; the residue was diluted with water and neutralized with 2 N HCl. The product was extracted with ethyl e (3X100 mL). The combined organic layer was washed with water, then brine, dried over Na2804, and evaporated, to give crude 2-amino-4,6—diisopropoxy—nicotinic acid as a light yellow solid. Yield: 1.48 g (98%, crude).

To a solution of 2-amino—4,6—diisopropoxy-nicotinic acid (1.48 g, 5.83 mmol) in THF (30 mL) were added EDCI (1.34 g, 6.99 mmol), HOBt (0.94 g, 6.99 mmol), NMM (0.70 g, 6.99 mmol) and liquid NH3 (10 mL). Then, the reaction mixture was d at room temperature for 24 hours. Then, water (100 mL) was added and the products were extracted with ethyl acetate (2X200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous NaZSO4. Removal of solvent gave crude 2—amino—4,6—diisopropoxy- nicotinamide as a yellow oil. Yield: 450 mg (26%, crude).

To a solution of 2—amino-4,6-diisopropoxy-nicotinamide (450 mg, 1.78 mmol) and methyl(2-pyrrolidin-1—y|-ethoxy)—benzaldehyde (440 mg, 1.78 mmol) in N,N-dimethyl acetamide (10 mL) were added NaH803 (790 mg, 4.44 mmol) and p-TSA (845 mg, 4.44 mmol). The reaction mixture was heated at 120 °C for 16 hours, then cooled to room temperature. The solvent was removed under reduced pressure. Then, water (100 mL) was added and stirred for 30 min at room temperature. The ted solids were filtered and dried to give crude product, which was purified by the flash system, using 2% methanol in romethane, to give a yellow oil, which dissolved in ether. 2N HCl in ether was added, and the separated solids were filtered and dried to give the hydrochloride salt of the title compound as a yellow solid. Yield: 59 mg (6%). 1H NMR (400 MHz, DMSO-ds):610.7(br s, 1H), 7.88 (s, 2H), 6.31 (s, 1H), 5.41 (m, 1H), 4.80 (m, 1H), 4.14 (t, J = 4.8 Hz, 2H), 3.61 (m, 2H), 3.16 (m, 4H), 2.34 (s, 6H), 2.03 (m, 2H), 1.91 (m, 2H), 1.32 (s, 6H), 1.30 (s, 6H). MS (ES) m/z: 481.18 (M+1).

Example 97. Preparation of (S)—2-(3,5—Dimethyl((5-oxopyrrolidin y|)methoxy)pheny|)—5,7~dimethoxyquinazolin—4(3H)—one /o C I N\ /O O To a solution of (S)-5—(hydroxymethyl)pyrro|idinone (3.85 g, 33.5 mmol) in acetonitrile (60 mL) under nitrogen was added PPh3 (9.16 g, 34.8 mmol).

The mixture was cooled to 0 °C and CBr4 (11.55 g, 34.8 mmol) added dropwise as a solution in acetonitrile (40 mL) over 15 minutes. Then, the reaction mixture was warmed to room temperature and stirred for 18 hours. The mixture was then concentrated and heptane (100 mL) and water (100 mL) added. After ng for 1 hour, the solids were filtered and washed with 1:1 heptane/water (100 mL). The filtrate layers were separated and the aqueous layer extracted with EtZO (2X100 mL) and CHCl3 (2X100 mL). The combined c phase was dried over anhydrous NaZSO4, filtered, concentrated, and purified by silica gel chromatography, eluting with 100% CHCl3 to 10% MeOH/CHClg, to afford (S) (bromomethyl)pyrrolidin-2—one as a white solid (3.15 g, 53%).

To a solution of 4-hydroxy-3,5—dimethylbenzaldehyde (2.65 g, 17.7 mmol) in DMF (100 mL) was added K2C03 (3.66 g, 26.6 mmol). The mixture was stirred at room temperature under en for 30 minutes. Then, a solution of (S)—5-(bromomethyl)pyrrolidin—2-one (3.15 g, 17.7 mmol) in DMF (100 mL) was added, and the mixture heated at reflux for 16 hours. The mixture was then concentrated, ethyl acetate (250 mL) added, and the organic phase washed sequentially with water (2X150 mL), and brine (200 mL), dried (NaZSO4), filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate, followed by a second tography, eluting with 1:1 CH2Cl2/92z7z1 MeOH/concentrated NH4OH to 100% 92:7:1 CHCI3/MeOH/concentrated NH4OH, to afford (S)—3,5- dimethyl((5-oxopyrrolidinyl)methoxy)benzaldehyde as a white solid (0.200 g, A mixture of (S)-3,5-dimethyl((5-oxopyrrolidin yl)methoxy)benzaldehyde (0.200 g, 0.81 mmol), 2-amino—4,6— dimethoxybenzamide (0.159 g, 0.81 mmol), NaH803 (0.093 g, 0.89 mmol), and p— TsOH (0.015 g, 0.08 mmol) in DMA (10 mL) was heated at 150 °C for 48 hours.

The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (2XZ00 mL), dried over anhydrous Na2804, ed, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2C|2I 92:7:1 CHCI3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 6:3:1 CHCI3/MeOH/concentrated NH4OH, to afford the title compound as an off-white solid (0.108 g, 31%). 1H NMR (300 MHz, DMSO-d6)2511.85(s, 1H), 7.79—7.91 (m, 3H), 6.74 (d, J: 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), .94 (m, 4H), 3.84 (s, 3H), 3.63-3.75 (m, 2H), 2.30 (s, 6H), 2.09-2.27 (m, 3H), .00 (m, 1H). APCI MS m/z 424 [M+H]+.

Example 98. Preparation of 2—(4—((4-lsopropylpiperazin—1-yl)methyl)phenyl)~5,7- dimethoxyquinazolin-4(3H)—one /O O To a mixture of 4—(bromoethyl) benzaldehyde (0.200 g, 1.0 mmol) and K2CO3 (0.277 g, 2.0 mmol) in DMF (5 mL) was added N—isopropylpiperazine (0.129 g, 1.0 mmol) and the reaction was stirred at room temperature for 5 hours, then concentrated in vacuo. The resulting mixture was diluted with H20 and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2804, filtered, and concentrated in vacuo to afford 4-((4—lsopropylpiperazin-1— yl)methyl)benzaldehyde (0.240 g, 97%).

A mixture of 4-((4-isopropylpiperazinyl)methyl)benzaldehyde (0.240 g, 0.97 mmol), NaH803 (0.155 g, 1.50 mmol), and p—TsOH (0.019 g, 0.10 mmol) was added to a solution of 2-amino—4,6—dimethoxybenzamide (0.190 g, 0.97 mmol) in DMA (7 mL). The on was stirred at 130 °C overnight. Then, the mixture was diluted with H20 and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous N32804, ed, and concentrated in vacuo. Purification by flash tography on silica gel, eluting with 2% to 10% MeOH/CHZClz, afforded the title compound (0.122 g, 30%) as a light yellow solid. 1H NMR (300 MHz, DMSO-de):612.02(s, 1H), 8.12 (d, J: 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.74 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.51 (s, 2H), 2.54-2.71 (m, 1H), 2.27—2.44 (m, 8H), 0.95 (d, J = 6.4 Hz, 6H). ESl MS m/z 423 [M+H]+.

Example 99. Preparation of N-(1-(4-(5,7—Dimethoxyoxo-3,4-dihydroquinazolin- 2-yl)benzyl)piperidin-4—yl)-N-isopropylacetamide /©Erfi@ik To a mixture of 4-(bromoethyl) benzaldehyde (0.840 g, 4.2 mmol) and K2C03 (1.75 g, 12.6 mmol) in DMF (15 mL) was added N—isopropyl-N— (piperidinyl)acetamide (0.92 g, 4.2 mmol) and the on was stirred at room temperature 5 hours, then trated in vacuo. The resulting mixture was diluted with H20 and extracted with EtOAc. The organics were washed with brine, dried over anhydrous N32804, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CHZCIZ, afforded N—(1-(4-formylbenzy|)piperidin—4—y|)-N-isopropylacetamide (0.770 g, 61%).

A mixture of N-(1—(4-formy|benzyi)piperidin—4—yI)—N- isopropylacetamide (0.770 g, 2.5 mmol), NaH803 (0.350 g, 3.3 mmol), and p- TsOH (0.100 g, 0.51 mmol) was added to a solution of 2-amino-4,6- dimethoxybenzamide (0.500 g, 2.5 mmol) in DMA (20 mL). The reaction was stirred at 130 °C for 5 hours and concentrated in vacuo. The residue was diluted with H20 and saturated NaHCOs, then extracted with . The organics were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% HZCIZ, afforded the title compound (0.670 g, 56%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6)2612.02(s, 1H), 8.13 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 1.9 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 3.85-3.95 (m, 7H), 3.43—3.71 (m, 3H), 2.55—3.00 (m, 3H), 1.97-2.09 (m, 5H), 1.70—1.77 (m, 1H), 1.58-1.61 (m, 1H), 1.25—1.30 (m, 4H), 1.11-1.13 (m, 3H). E8! M8 m/z 479 [M+H]+.

Example 100. Preparation of 2-(4—((4-(Isopropylamino)piperidin y|)methy|)phenyl)—5,7-dimethoxyquinazolin-4(3H)—one /o o A solution of 2-(4-((4—isopropylpiperazin—1~yl)methyl)phenyI)-5,7- dimethoxyquinazoiin—4(3H)-one (0.470 g, 0.98 mmol) in 2N HCI (20 mL) was refluxed for 3 days. The resulting mixture was basified with 2N NaOH and ted with . The cs were washed with brine, dried over anhydrous , filtered and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCIg/MeOH/concentrated NH4OH in CHgCig, afforded the title nd (0.090 g, 21%) as a light yellow solid. 1H NMR (300 MHz, DMSO-ds): 6 8.12 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 2.3 Hz, 1H), 6.53 (d, J: 2.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.50 (s, 2H), 2.86-2.92 (m, 1H), 2.73—2.77 (m, 2H), 1.85—2.01 (m, 2H), 1.72—1.77 (m, 2H), 1.09-1.38 (m, 4H), 0.94 (d, J = 6.2 Hz, 6H).

ESl/APCI Ms m/z 437 [M+H]+. e 101. Preparation of 2-(4-((1H—Tetrazol-5—yl)methyl)phenyl)-5,7— dimethoxyquinazolin-4(3H)—one \ ,IN /0 N\ NTN /O O To a solution of 4—cyanomethyl c acid methyl ester (2.63 g, 15 mmol) in anhydrous toluene (100 mL) was added sodium azide (1.95 g, 30 mmol) and triethylamine hydrochloride (4.13 g, 30 mmol). The reaction mixture was stirred at 100 °C for 24 hours under nitrogen. The reaction mixture was cooled to room ature, then extracted with water (2X100 mL). The aqueous layer was acidified with concentrated HCl to pH imately 4. The white solid was filtered off, washed with water, and dried under vacuum at 40 °C overnight, to give methyl-4—(1H-tetrazolylmethyl) benzoate (2.88 g, 88%) as an off—white solid.

Lithium aluminium hydride (0.142 g, 3.75 mmol) was taken in a dry, three—necked flask, fitted with a reflux condenser. Anhydrous ether (10 mL) was added. A solution of methyl(1H-tetrazolylmethyl) te (0.654 g, 3.0 mmol) in anhydrous THF (5 mL) was added dropwise. After the addition was complete, the mixture was heated to reflux for 2 hours. Then, the reaction mixture was cooled to 0 °C and quenched by cautious addition of water (10 mL) and 15% sodium hydroxide solution (10 mL). The reaction e was stirred for 30 minutes and then allowed to warm to room temperature. The aqueous phase was acidified to pH 4 and left for 2 days. A white precipitate was formed and filtered off, washed with water, and dried under vacuum, to give [4-(1H—tetrazol-5— ylmethyl)—phenyl]-methanol as a white solid. Yield: 0.290 g (51%). lBX (0.437 g, 1.562 mmol) was dissolved in anhydrous DMSO (5 mL) and [4-(1H-tetrazol—5—ylmethyl)—phenyl]—methanol (0.270 g, 1.562 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 4 hours. Water (20 mL) was added. The white precipitate was filtered off, washed with water, and dried under vacuum. The crude compound was mixed with methanol (20 mL) and stirred for 30 minutes, before being filtered. The filtrate was concentrated to give 4—(1H—tetrazol-5ylmethyl)-benzaldehyde as a white solid.

Yield: 0.267 g (99%). To a solution of 2—aminc—4,6-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethyl acetamide (5 mL) were added 4-(1H—tetrazol- hyl)-benzaldehyde (0.260 g, 1.4 mmol), sodium hydrogen sulfite (58.5%, 0.159 g, 0.88 mmol) and p—toluenesulfonic acid (19 mg, 0.08 mmol). The reaction mixture was stirred at 150°C for 3 h, then cooled to room temperature. Water (40 mL) was then added. A yellow precipitate was formed and filtered off, washed with water, and small amount of ol. It was triturated with 10% methanol in ether to give 0.107 g of solid, which was further purified by preparative HPLC, to give the title compound (0.082 g, 28%) as a white solid. MS (ES) m/z: 365.1 (M+1).

MP 295-296°C.

Example 102. Preparation of 1—(2—(4—(5,7—Dimethoxy-4—oxo-3,4-dihydroquinazolin- 2—yl)—2,6-dimethylphenoxy)ethyl)pyrrolidine—2,5-dione /o o To a solution of 2—[4—(2—hydroxy—ethoxy)-3,5-dimethyl-phenyl]—5,7- dimethoxy-3H—quinazolinone (0.50 g, 1.35 mmol) in anhydrous THF (20 mL) were added triphenyl phosphine (0.53 g, 2.02 mmol), pyrrolidine-2,5-dione (0.20 g, 2.02 mmol), and N,N-diisopropylethyl amine (0.44 g, 3.38 mmol). To this stirred solution was added lazodicarboxylate (0.35 g, 2.02 mmol). The reaction mixture was d at room temperature for 8 hours under nitrogen. Ethyl acetate (400 mL) was added. The c phase was ted, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2804. The solvent was removed under reduced pressure. The crude material was purified by the Simpliflash system (4:96 methanol:CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.3 g. (49%). 1H NMR (400 MHz, CDCl3): 5 9.30 (br s, 1H), 7.66 (s, 2H), 6.82 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 1.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.92 (s, 4H), 2.78 (s, 4H), 2.31 (s, 6H). MS (ES) m/z: 452.51 (M+1) (100%). e 103. Preparation of Benzyloxy)ethoxy)~5-methoxy(pyridin—4- yl)quinazolin-4(3H)-one To a stirred solution of 2—amino—4,6-difluoro-benzamide (0.50 g, 2.9 mmol) and pyridine—4-carbaldehyde (0.35 g, 3.2 mmol) in N,N-dimethylacetamide (10 mL) were added sodium hydrogen sulfite (0.63 g, 3.5 mmol) and p- toluenesulfonic acid (0.06 g, 0.3 mmol); the reaction mixture was stirred at 115 °C for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off to obtain 5,7-difluoro—2-pyridin-4—yl-3H— quinazolin-4—one as a yellow solid, which was used in the next step without further purification. Yield: 0.4 g (53%).

To a sion of 5,7-difluoro—2—pyridinyl-3H—quinazolin—4-one (0.20 g, 0.80 mmol) in DMF (3 mL) was added sodium ide in methanol (0.43 g, 8.0 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water was added, the mixture was acidified with acetic acid to pH imately 4-5, and the precipitated solid was filtered off to obtain 7-fluoro—5— methoxy—2-pyridin—4-yl-3H—quinazolin-4—one as a yellowish solid. Yield: 0.20 g (83%).

To a solution of 2—benzyloxy-ethanol (2 mL) in dimethyl sulfoxide (3 mL) was added sodium hydride (0.30 g, 7.4 mmol) in portions, and the reaction mixture was stirred at room temperature for 45 minutes. To this mixture was added 7-fluoro—5-methoxypyridin—4-yl—3H—quinazolin—4—one (0.20 g, 0.74 mmol) and the reaction mixture was heated at 80 °C for 16 hours. Water was added, the mixture was acidified with acetic acid to pH approximately 4-5, and the precipitated solid was filtered off, to obtain a crude product, which was purified by ative HPLC to obtain the title compound as a light yellow solid. Yield: 0.12 g (40%). MP 228.2-229.9°C. 1H NMR (400 MHz, DMSO-de): 612.29 (s, 1H), 8.77 (d, 2H), 8.08 (d, 2H), 7.36 (m, 5H), 6.82 (s, 1H), 6.62 (s, 1H), 4.58 (s, 2H), 4.32 (t, 2H), 3.87 (s, 3H), 3.83 (t, 2H). MS (ES+) m/z: 404.51 (M+1).

Example 104. Preparation of 2-(2,6-Dimethylpyridin~4-yl)—5,7- dimethoxyquinazolin-4(3H)—one A solution of 2,6-lutidine N—oxide (24.0 g, 0.20 mol) in anhydrous dichloromethane (400 mL) was added to trimethyloxonium tetrafluoroborate (29.6 g, 0.20 mol) at room temperature under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 3 hours. The mixture was trated in vacuo to give the crude product, 1—methoxy-2,6—dimethyl- nium tetrafluoroborate.

The crude product was dissolved in MeOH (300 mL) and heated to reflux under nitrogen. Then, a solution of ammonium persulfate (14.2 g, 0.06 mol) in water (57 mL) was added. The mixture was stirred under reflux for 16 hours; TLC showed completion of the reaction. Half of the solvent was removed in vacuo, then quenched with 10% aqueous NaOH solution to pH 7, and evaporated to dryness in vacuo. The residue was dissolved in methanol and filtered, the filtrate was concentrated in vacuo, and the crude compound was purified by column chromatography (silica gel 0 mesh; 5-15 % methanol in CHzClz as eluent) to give oxymethyl—2,6—dimethylpyridine as a white solid. Yield: 11.0 g (40.0 4-Hydroxymethyl-2,6-dimethylpyridine (1.00 g, 7.28 mmol) was dissolved in ethanol (20 mL), and activated MnOz (2.24 g, 21.8 mmol) was added; the reaction mixture was refluxed for 17 hours. The mixture was cooled and concentrated, purified by column chromatography a gel 230-400 mesh; 20% ethyl e in hexanes as ) to give 2,6—dimethyl—4-pyridinecarboxaldehyde as a yellow oil. Yield: 0.14 g (14 %).

To a solution of 2,6—dimethylpyridinecarbaldehyde (0.14 g, 1.00 mmol) in N,N-dimethyl acetamide (10 mL) were added 2-amino-4,6— oxybenzamide (0.20 g, 1.00 mmol), sodium hydrogen sulfite (0.21 g, 2.00 mmol), and p—toluenesulfonic acid (0.28 g, 1.50 mmol). The reaction mixture was d at 110 °C for 16 hours under nitrogen. After cooling to room temperature, solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated NaHC03 solution (30 mL), water (30 mL), and brine (30 mL), and dried over anhydrous sodium sulfate. Solvent was ated, and the residue was purified by column chromatography a gel 230-400 mesh; 25% methanol in dichloromethane as eluent) to give the title compound as a yellow solid. Yield: 0.030 g (10%). MP 291—292°C. 1H NMR (400 MHz, CDCI3): 8 9.86 (br s, 1H), 7.60 (s, 2H), 6.87 (d, J = 2.2 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.66 (s, 6H). MS (ES) m/z: 312.50 (M+1) (100%).

Example 105. Preparation of 2—(2,6-Dimethylpyridin-4—yl)methoxy—7—(2— methoxyethoxy)quinazolin-4(3H)—one /0 o To a suspension of 2,6-dimethyl—pyridinyl)-methanol (1.00 g, 7.30 mmol) in acetonitrile (20 mL), 1,2~benziodexol—3(1H)—one—1—hydroxyoxide (IBX) (2.00 g, 7.30 mmol) was added and the reaction mixture was refluxed for 6 hours.

The solid was filtered off and washed with itrile. The te was evaporated in vacuo to give 2,6-dimethyl-pyridinecarbaldehyde as a brown liquid. Yield: 0.81 g (82%).

To a stirred solution of 2—amino-4,6-difluoro-benzamide (1.03 g, 6.00 mmol) and 2,6-dimethyl-pyridine—4-carbaldehyde (0.81 g, 6.00 mmol) in MN- dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt%, 1.31 g, 7.20 mmol), and p—toluenesulfonic acid monohydrate (0.11 g, 0.60 mmol) were added and the reaction mixture was stirred at 115 °C for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered, to give 2—(2,6-dimethyl-pyridinyl)~5,7-difluoro-3H—quinazolin—4-one as a yellow solid, which was used in the next step without further purification. Yield: 0.72 g (42%).

To a suspension of 2-(2,6-dimethyl—pyridin—4-yl)—5,7-difluoro—3H— quinazoiin-4—one (0.72 g, 2.51 mmol) in DMF (10 mL), a solution of sodium methoxide in methanol (25 wt%, 1.36 g, 25.1 mmol) was added and the reaction mixture was stirred at room ature for 16 h. Water was added, the mixture was acidified to pH approximately 4—5 with acetic acid, and the precipitated solid was filtered and dried under vacuum to give 2-(2,6—dimethyl-pyridinyl)fluoro— -methoxy-3H—quinazolin-4~one as a light yellow solid. Yield: 0.28 g (37%).

To a solution of oxyethanol (3 mL) in yl sulfoxide (8 mL), sodium hydride (60% suspension in mineral oil, 0.40 g, 9.40 mmol) was added in portions and the reaction mixture was stirred at room temperature for 1 hour. To this reaction mixture was added 2-(2,6-dimethyl-pyridin-4—y|)fluoro—5- methoxy—3H—quinazolinone (0.28 g, 0.94 mmol) and the reaction mixture was stirred at 90 °C for 16 hours. Water was added, acidified to pH approximatley 4—5 with acetic acid, and the precipitated solid was ed to give crude t, which was purified by preparative HPLC, to obtain the title compound as a white solid. Yield: 0.12 g (36%). MP 228.8-230.4°C. MS (ES) m/z: 356.05 (M++1). 1H NMR (400 MHz, CDCI3): 510.45 (s, 1H), 7.65 (s, 2H), 6.85 (d, J = 1.6 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 4.27 (t, J = 4.8 Hz, 2H), 3.97 (s, 3H), 3.82 (t, J = 4.8 Hz, 2H), 3.49 (s, 3H), 2.66 (s, 6H).

Example 106. Preparation of 2—(2,6-Dimethylpyridin—4-yl)~5,7-bis(2- methoxyethoxy)quinazolin—4(3H)—one To a suspension of 2,6-dimethyl—pyridin-4—yl)-methanol (1.00 g, 7.30 mmol) in itrile (20 mL), 1,2—benziodexol—3(1H)—one—1-hydroxy-1—oxide (lBX) (2.00 g, 7.30 mmol) was added and the reaction mixture was refluxed for 6 hours.

The solid was filtered off and washed with acetonitrile. The filtrate was evaporated in vacuo, to give 2,6—dimethyl-pyridinecarbaldehyde as a brown liquid. Yield: 0.81 g (82%).

To a d solution of 2-amino-4,6—difluoro-benzamide (1.03 g, 6.00 mmol) and methyl-pyridinecarbaldehyde (0.81 g, 6.00 mmol) in MN— yl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt%, 1.31 g, 7.20 mmol) and p—toluenesulfonic acid drate (0.11 g, 0.60 mmol) were added and the reaction mixture was stirred at 115 °C for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered to give 2—(2,6—dimethyl-pyridin—4-yl)—5,7-difluoro—3H—quinazolinone as a yellow solid, which was used in the next step without further purification. Yield: 0.72 g (42%).

To a suspension of 2—(2,6-dimethyl-pyridinyl)-5,7—difluoro-3H— quinazolinone (0.72 g, 2.51 mmol) in DMF (10 mL), a solution of sodium methoxide in methanol (25 wt%, 1.36 g, 25.1 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water was added, the mixture was acidified to pH imately 4-5 with acetic acid, and the precipitated solid was filtered and dried under vacuum, to give 2—(2,6-dimethyl- pyridin—4—yl)—7-fluoromethoxy-3H—quinazolin—4—one as a light yellow solid. Yield: 0.28 g (37%).

To a solution of oxyethanol (3 mL) in dimethyl sulfoxide (8 mL), sodium hydride (60% suspension in mineral oil, 0.40 g, 9.40 mmol) was added in ns and the reaction mixture was stirred at room temperature for 1 hour. To this reaction mixture was added 2—(2,6-dimethyl-pyridinyl)—7—fluoro—5~ methoxy-3H—quinazolinone (0.28 g, 0.94 mmol); the reaction mixture was stirred at 90 °C for 16 hours. Water was added, the mixture was acidified to pH approximatley 4-5 with acetic acid, and the precipitated solid was filtered, to give crude product, which was purified by preparative HPLC to obtain the title compound. Yield: 0.03 g (8%). MP 149.8-151.4°C. MS (ES) m/z: 400.13 (M++1). 1H NMR (400 MHz, CDCI3): 5 7.54 (s, 2H), 6.85 (s, 1H), 6.61 (s, 1H), 4.24 (m, 4H), 3.87 (t, J = 5.2 Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.49 (br s, 6H), 2.65 (s, 6H).

Example 107. ation of 2-(2,6-Dimethylpyridinyl)—7—methoxy-5—(2- (pyrrolidin—1-yl)ethoxy)quinazolin-4(3H)—one To a solution of 2,6—dimethyl-pyridine—4—carbaldehyde (0.99 g, 7.32 mmol) and 2—amino-4,6-difluorobenzamide (1.26 g, 7.32 mmol) in N,N-dimethyl acetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt%, 1.59 g, 8.78 mmol) and p—toluenesulfonic acid (0.21 g, 1.09 mmol). The reaction mixture was stirred at 115 °C for 16 hours under nitrogen. After cooling to room temperature, the solvent was evaporated under reduced pressure. Water (50 mL) was added, the precipitated solid was filtered, washed with water, and dried under vacuum, to give 2—(2,6—dimethyl-pyridin—4—yl)-5,7-difluoro—3H—quinazolinone as a yellow solid. Yield: 0.63 g (30%).

To a solution of 2-pyrrolidinyl-ethanol (5.09 g, 44.2 mmol) in DMF (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.88 g, 22.1 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this e was added 2—(2,6-dimethyl—pyridinyl)—5,7— ro—3H—quinazolin-4—one 0.63 g, 2.21 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was neutralized, to pH approximately 6 with acetic acid. Solvent was evaporated, and the residue was dissolved in ethyl acetate, washed with water, and dried over ous sodium e, and concentrated in vacuo. The crude compound was purified by the Simpliflash system (0-4% methanol in CHZClz as eluent) to give -dimethyl—pyridinyl)fluoro—5-(2-pyrrolidin-1~yl~ethoxy)— 3H—quinazolinone as a yellow solid. Yield: 0.61 g (72%).

To a solution of 2-(2,6-dimethyI-pyridinyl)fluoro(2—pyrrolidin- 1-yl-ethoxy)—3H—quinazolin—4-one (0.30 g, 0.80 mmol) in anhydrous DMF (5 mL) was added a solution of sodium methoxide in methanol (25 wt%, 0.43 g, 8.00 mmol) and the reaction mixture was stirred at 70°C for 16 h. After cooling to room temperature, water (10 mL) was added, and the mixture was neutralized to pH approximatley 6 with acetic acid. The solvent was evaporated, and the residue was purified by the Simpliflash system (2% methanol in CH2CI2 and then 4% 7.0 M a in methanol and CH2C|2 as ) to give the title compound as a yellow solid. Yield: 0.100 g (32%). MP 190-191°C. 1H NMR (400 MHz, CDCI3)I 6 7.59 (s, 2H), 6.86 (d, J =1.95 Hz, 1H), 6.53 (d, J = 1.95 Hz, 1H), 4.25 (t, J = 6.05 Hz, 2H), 3.93 (s, 3H), 3.03 (t, J = 6.24 Hz, 2H), 2.69 (br s, 4H), 2.64 (s, 6H), 1.93—1.70 (m, 4H). MS (ES+) m/z: 395.22 (M+1) and 298.12 (100%).

Example 108. Preparation of -Dimethylpyridin-4—yl)—6-((4—methylpiperazin~1— yl)methyl)quinazolin-4(3H)—one [041 1] To a mixture of 5—methylnitrobenzoic acid (45.0 g, 0.248 mol) and potassium carbonate (138.2 g, 1.0 mol) in acetonitrile (700 mL), methyl iodide (78 mL, 1.25 mol) was added. The reaction mixture was stirred at room temperature for 12 hours, then the solution was filtered. The filtrate was concentrated under reduced pressure. The resulting solid was ved in ethyl acetate and washed with water and brine. The crude 5—methylnitrobenzoic acid methyl ester was used in the next step without r purification. Yield: 27.1 g (56 %). 5-Methylnitrobenzoic acid methyl ester (27.1 9, 138.8 mmol) was dissolved in carbon tetrachloride (500 mL), and N—bromosuccinimide (29.6 g, 166.6 mmol) was added, followed by benzoyl peroxide (6.72 g, 27.7 mmol). The mixture was illuminated and gently refluxed for 4 hours. Then, the mixture was cooled and concentrated, then purified by column chromatography silica gel 230- 400 mesh; 10% ethyl acetate in hexanes as ) to give 5—bromomethyl nitrobenzoic acid methyl ester. Yield: 17.9 g (47%).

To a on of 5-bromomethyl—2-nitrobenzoic acid methyl ester (3.00 g, 10.9 mmol) in CH2Cl2 (100 mL) was added triethylamine (3.30 g, 33.0 mmol) and 1—methylpiperazine (3.30 g, 33.0 mmol). The mixture was heated at 50 °C under nitrogen for 16 hours, then concentrated to give crude 5-(4- methylpiperazin—1—y|methyl)—2-nitrobenzoic acid methyl ester, which was purified by column chromatography (silica gel 0 mesh; 1~5 % ol in dichioromethane as eluent). Yield: 3.0 g (93%). It was further converted to its hydrochloride salt (3.7 g) by stirring in 1 M HCI in ether and was isolated by tion.

To a solution of 5-(4-methylpiperazin—1—y|methyI)nitrobenzoic acid methyl ester hydrochloride salt (3.70 g, 10.0 mmol) in acetic acid (50 mL) was added iron powder (1.80 g, 32.1 mmol), and the mixture was stirred at 70 °C for 2 hours; TLC indicated completion of the reaction. The mixture was cooled and trated; the residue was taken in 7 N ammonia in methanol (50 mL) and filtered. The filtrate was evaporated to dryness and ed by column chromatography (silica gel 230-400 mesh; 5-10% methanol in dichloromethane as eluent). Yield: 4.3 g ). The crude 2—amino(4—methyl-piperazin ylmethyl)benzoic acid methyl ester was used in the next step without further purification.

To a suspension of 2-amino(4-methyl-piperazin ylmethyl)benzoic acid methyl ester (4.30 g, 10.0 mmol) in water (30 mL) and methanol (10 mL) was added lithium hydroxide (1.26 g, 30.0 mmol); the mixture was stirred at room temperature for 12 hours. An additional amount of lithium hydroxide (0.6 g, 15.0 mmol) was added, and heated at 40 °C for 15 hours; TLC indicated tion of the reaction. The mixture was cooled, concentrated, the residue was adjusted to pH ~5 with 6 N HCI, and evaporated to dryness, to provide crude 2—amino-5—(4—methyl-piperazin—1—y|methyl)benzoic acid. Yield: 6.2 9, along with inorganic salt. It was used in the next step without further purification.

To a suspension of 2—amino(4-methyI—piperazin ylmethyl)benzoic acid (crude 1.28 g, 3.00 mmol) in THF (18 mL) and DMF (7 mL), EDCI (0.77 g, 4.00 mmol), and HOBT (0.50 g, 3.30 mmol) were added and stirred at room temperature for 20 minutes. Then, N-methylmorpholine (0.33 g, 3.30 mmol) and NH4OH (aq. 50 %v/v, 3.50 mL, 50.0 mmol) were added. The mixture was stirred at room temperature for 48 hours. The solvent was evaporated, the residue was ed by column chromatography (silica gel 230-400 mesh; 5-10% 2 M ammonia in methanol and dichioromethane as ) to give 2-amino(4- methyl—piperazinylmethyl)benzamide as a white solid. Yield: 0.416 g (55 % for two steps).

To a solution of 2,6—dimethylpyridinecarbaldehyde (0.14 g, 1.00 mmol) in N,N—dimethyl acetamide (8 mL) were added 2-amino(4-methyl— piperazinylmethyl)benzamide (0.25 g, 1.00 mmol), sodium hydrogensulfite (0.18 g, 1.20 mmol), and p-toluenesulfonic acid (0.057 g, 0.30 mmol). The reaction mixture was stirred at 115 °C for 20 hours under nitrogen, then cooled to room ature. Solvent was evaporated under reduced pressure. The residue was ved in dichloromethane, washed with sat. NaHC03, water, then brine, and dried over anhydrous sodium sulfate. Solvent was evaporated and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-3% 7 M ammonia in ol and dichloromethane as eluent) to give the title compound. Yield: 0.035 g (9.6%). MP 229-230°C. 1H NMR (400 MHz, CDClg): 8 8.30 (br s, 1H), 7.88 (s, 2H), 7.84 (m, 2H), 3.66 (s, 2H), 2.72 (s, 6H), 2.50 (br s, 8H), 2.30 (s, 3H). MS (ES) m/z: 364.17 (M+1), 182.67 (100%).

Example 109. Preparation of 2-(2,6—Dimethylpyridin—4~y|)methoxy-7—(2~ phenoxyethoxy)quinazolin~4(3H)—one C 1: .NH O O To a solution of 2-phenoxy—ethanol (0.90 g, 6.50 mmol) in DMSO (5 mL) was added sodium hydride (60% in mineral oil, 0.16 g, 4.00 mmol) in small ns. The on mixture was d at room temperature under nitrogen for 1 hour. 2-(2,6-Dimethyl-pyridin-4—yl)fluoro—5-methoxy-3H—quinazolin—4-one (0.20 g, 0.67 mmol) was added and stirring continued at 90 °C for 17 hours. The reaction was then cooled to room temperature, water (100 mL) was added, and was extracted with ethyl acetate (200 mL). The organic phase was washed with brine and dried over anhydrous Na2804. Solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% ol in CH2C|2 as eluent) to give the title compound as a white solid. Yield: 70 mg (25%). MP 223-224°C. 1H NMR (400 MHz, CDCI3): 8 11.35 (s, 1H), 7.75 (s, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.02—6.97 (m, 3H), 6.91 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 1.6 Hz, 1H), .47 (m, 2H), 4.41—4.39 (m, 2H), 3.97 (s, 3H), 2.67 (s, 6H). M3 033*) m/z: 418.08 (M+1).

Example 110. ation of 2-(2,6—Dimethylpyridinyl)-7—methoxy—5-(2— phenoxyethoxy)quinazolin-4(3H)—one /O N\ / J/O O A solution of 2,6—lutidine N-oxide (41.6 g, 0.337 mol, 1.0 equiv.) in dry DCM (650 mL) was added to a flask containing trimethyloxonium tetrafluoroborate (50.0 g, 0.337 mol, 1.0 equiv.) at room temperature. under a nitrogen atmosphere. The mixture was d at room temperature for 3.0 hours, then concentrated in vacuo to give 78 g of crude 4—hydroxymethyl~2,6— dimethylpyridine. The crude product was dissolved in methanol (500 mL) and the solution was heated to reflux under a nitrogen atmosphere, then a solution of ammonium persulfate (24.6 g, 0.101 mol) in water (100 mL) was added dropwise.

The mixture was stirred at reflux for 16 hours; TLC indicated te reaction.

Half of the solvents were removed in vacuo, then quenched with 10% NaOH solution to pH approximately 7, and evaporated to dryness. The residue was dissolved in ol and filtered, the filtrate was concentrated in vacuum, and purified by column chromatographt (eluting with methanol: DCM = 5—15%) to give the title compound as a white solid. Yield: 24.7 g (52%). 4-Hydroxymethyl-2,6~dimethylpyridine (24.7 g, 180 mmol, 1.0 equiv.) was dissolved in DMSO (200 mL), and IBX (53.0 g, 189 mmol, 1.05 equiv.) was added in ns, the mixture was stirred at room temperature for 2 hours; TLC indicated complete reaction. The mixture was filtered, washed with water and ether. The filtrate was extracted with ether (4 x 150 mL); the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography (20% ether in hexanes as ) to give 2,6—dimethyl4- pyridinecarboxaldehyde as a yellow oil. Yield: 20.0 g (82%).

To a solution of 2,6-dimethyl—pyridine—4—carbaldehyde (5.0 g, 36.5 mmol) and 2—amino-4,6-difluorobenzamide (6.28 g, 36.5 mmol) in N,N—dimethyl acetamide (80 mL) were added sodium hydrogen sulfite (7.95 g, 43.8 mmol) and p—toluenesulfonic acid (0.7 g, 3.65 mmol). The reaction mixture was stirred at 115 °C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with water, the precipitate was collected by filtration, washed with sat. NaH003 and brine, and dried in vacuo to give 2-(2,6-dimethylpyridin yl)—5,7-difluoro-3H-quinazolin-4—one as a white solid. Yield: 2.82 g (26.8%).

To a solution of 2-phenoxyethanol (4.81 g, 34.8 mmol) in DMF (20 mL) was added sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol) in ns and the reaction mixture was stirred at room temperature for 1 hour. To this mixture was added —dimethylpyridiny|)-5,7-difluoro-3H- olin-4—one (0.50 g, 1.74 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (1 mL) was added, neutralized to pH approximatley 6-7 with acetic acid, concentrated, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The e was ed by column chromatography (eluted with 50% ethyl acetate in hexanes, then 5% methanol in DCM) to give 2-(2,6— ylpyridin—4-yl)-7—fluoro-5—(2—phenoxyethoxy)—3H-quinazolinone as a light yellow solid. Yield: 0.59 g (83%).

To a suspension of 2-(2,6—dimethylpyridin-4—yl)f|uoro(2- phenoxyethoxy)-3H-quinazolin—4-one (0.59 g, 1.45 mmol) in DMF (10 mL) was added a on of sodium methoxide in methanol (25 wt%, 3.15 g, 14.5 mmol) and the reaction mixture was stirred at approximatley 70-80 °C for 48 hours, then cooled to room temperature. Water (1 mL) was added, the mixture was neutralized to pH approximatley 6—7 with acetic acid, concentrated, dissolved in DCM, washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was passed through a column (eluted with 2% methanol in DCM), to give 0.12 g of the desired t. The crude product was washed with acetonitrile, then solubilized in dioxane, and precipitated by adding water to afford the title compound as a white solid. Yield: 70 mg (11%). 1H NMR (400 MHz, DMSO-ds): 612.08(br s, 1H), 7.77 (s, 2H), 7.31 (t, J = 7.81 Hz, 2H), 7.04 (d, J = 8.20 Hz, 2H), 6.96 (t, J = 7.42 Hz, 1H), 6.83 (d, J =,1.56 Hz, 1H), 6.69 (s, 1H), 4.40-4.53 (m, 2H), 3.90 (s, 3H), 3.33 ( s, 6H). M8 (E84) m/z: 418.14 (M+1)+; MP 172.3—173.2°C.

Example 111. Preparation of —Dimethylpyridinyl)~7—methoxy(2— methoxyethoxy)quinazolin—4(3H)—one To a solution of 2—methoxyethanol (2.65 g, 34.8 mmol) in DMF (38 mL) was added sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol) in portions and the reaction mixture was stirred at room temperature for 0.5 hours. To this mixture was added 2-(2,6—dimethylpyridinyl)—5,7—difluoro-3H— quinazolin—4-one (0.50 g, 1.74 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (1.5 mL) was added, the mixture was neutralized to pH approximatley 6—7 with acetic acid, concentrated, dissolved in ethyl acetate (200 mL), washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was washed with hexanes to give 2-(2,6- dimethylpyridinyl)fluoro(2-methoxyethoxy)-3H-quinazolinone) as a pale solid. Yield: 0.52 g (87 %).

To a suspension of 2-(2,6-dimethylpyridin—4-yl)—7-fluoro—5—(2- yethoxy)—3H—quinazolin-4—one (0.42 g, 1.22 mmol) in DMF (10 mL) was added a solution of sodium methoxide in methanol (25 wt%, 2.8 g, 12.8 mmol) and the reaction mixture was stirred at 70 °C for 16 hours, then cooled to room temperature. Water (1 mL) was added, the mixture was neutralized to pH approximately 6 with acetic acid, d with water (50 mL), and ted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and trated in vacuo, to give 0.30 g of crude compound. Further purification by crystallization in acetonezEtZO (1 :3) gave the title compound as a white solid. Yield: 91 mg (15%). 1H NMR (400 MHz, CDCl3): 6 .08 (br s, 1H), 7.60 (br s, 2H), 6.87 (d, J = 1.95 Hz, 2H), 6.55 (d, J = 1.95 Hz, 2H), 4.25 (t, J = 4.88 Hz, 2H), 3.93 (s, 3H), 3.83 (d, J = 4.29 Hz, 2H), 3.44 (s, 3H), 2.64 (s, 6H). MS (ES+) m/z: 356.11 (M+1)+ Example 112. Preparation of 2—(2,6-Dimethylpyridinyl)—5—methoxy—7-(2- (pyrrolidin—1~yl)ethoxy)quinazolin-4(3H)—one /0 o To a suspension of 2,6~dimethyl-pyridin-4—yl)-methanol (6.00 g, 0.043 mol) in acetonitrile (150 mL), 1,2—benziodexol-3(1I-I)—one—1-hydroxyoxide (lBX) (14.8 9, 0.0503 mol) was added and the reaction mixture was refluxed for 2 hours. The solid was ed off and washed with acetonitrile. The filtrate was evaporated in vacuo to give 2,6-dimethyl—pyridinecarbaldehyde as a brown . Yield: 4.30 g (72.7%).

To a stirred solution of 2-amino-4,6-difluoro-benzamide (4.00 g, 0.0237 mol) and 2,6-dimethyl—pyridine—4-carbaldehyde (3.20 9, 0.0237 mol) in N,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt%, 5.05 9, 0.0284 mol) and p—toluenesulfonic acid monohydrate (0.90 g, 4.74 mmol) were added and the reaction mixture was stirred at 130 °C for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered to give 2—(2,6—dimethyl—pyridinyl)—5,7—difluoro-3H—quinazolinone as a yellow solid, which was used in the next step without further cations. Yield: 3.70 g (42%).

To a sion of 2-(2,6~dimethyl-pyridinyI)-5,7-difluoro—3H— quinazolin-4—one (2.70 g, 9.4 mmol) in DMF (15 mL), a solution of sodium methoxide in methanol (25 wt%, 6.0 g, 28.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water was added, the mixture was acidified to pH approximatley 4-5 with acetic acid, and the precipitated solid was filtered and dried under vacuum to give crude - dimethyl-pyridin—4-yl)—7-fluoro—5—methoxy—3H—quinazolinone (2.40 g), which was further purified by column chromatography (silica gel 230-400 mesh; eluting with 2% methanol solution in dichloromethane) to yield pure compound as a light yellow solid. Yield: 0.35 g (12.4%).

To a solution of 2-pyrrolidiny|—ethanol (1.15 g, 10 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in l oil, 0.20 g, .0 mmol) was added in ns and the reaction mixture was stirred at room temperature for 20 minutes. To this on mixture was added 2—(2,6—dimethyl- pyridin—4-y|)fluoromethoxy—3H—quinazolinone (0.30 g, 1.0 mmol) and the reaction mixture was stirred at 75 °C for 16 hours. The on mixture was loaded onto a column and purified by column chromatography (silica gel 230-400 mesh; eluting with 5% 7.0 M ammonia in methanol solution in dichloromethane), to obtain the title compound as a white solid. Yield: 0.163 g ). MP 227- 229°C. MS (ES) m/z: 395.15 (M++1). 1H NMR (400 MHz, CDCI3): 6 7.78 (s, 2H), 6.87 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 4.25 (t, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.97 (t, J = 6.0 Hz, 2H), 2.66 (s, 6H), 2.63 (m, 4H), 1.83 (m, 4H).

Example 113. Preparation of 2-(2,6—Dimethylpyridinyl)—7-(2~isopropoxyethoxy)— -methoxyquinazolin-4(3H)—one /]\O/\/0 /N N\ \ To a suspension of 2-(2,6—dimethyl—pyridinyl)-5,7—difluoro-3H— quinazolin-4—one (0.97 g, 3.38 mmol) in anhydrous DMF (10 mL) was added a solution of sodium ide in methanol (25 wt%, 1.09 g, 20.3 mmol). The reaction mixture became clear. The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added, neutralized to pH approximatley 6 with aqueous 2N HCI. The ted solid was filtered, washed with water (50 mL), and dried under vacuum to give an off-white solid. Yield: 0.94 g (93%).

To a suspension of sodium hydride (60% suspension in mineral oil, 0.24 g, 6.00 mmol) in anhydrous DMSO (10 mL) was added 2-isopropoxy-ethanol at room ature under nitrogen. The mixture was stirred for 20 minutes at room ature, then 2—(2,6-dimethyl-pyridinyI)f|uoro—5-methoxy-3H— quinazolin-4—one (0.30 g, 1.00 mmol) was added and the reaction mixture was stirred at 80 °C for 16 hours, then cooled to room temperature. Water (50 mL) was added, and the mixture was extracted with a mixture of ethyl acetate and THF (4:1, 200 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate. Solvent was evaporated, and the crude compound was purified by the Simpliflash system (3:15:82 methanol, ethyl acetate and dichloromethane as eluent) to give the title compound as a white solid. Yield: 127 mg (33%). MP 188-189°C. 1H NMR (400 MHz, CDCI3): 511.14 (brs, 1H), 7.72 (s, 2H), 6.86 (d, J = 2.34 Hz, 1H), 6.59 (d, J = 2.34 Hz, 1H), 4.35 - 4.15 (m, 2H), 3.97 (s, 3H), 3.89 - 3.79 (m, 2H), 3.78 — 3.64 (m, 1H), 2.66 (s, 6H), 1.23 (d, J = 5.85 Hz, 6H). MS (ES+) m/z: 384.20 (100%). e 114. Preparation of 2-(2,6-dimethylpyridinyl)-5,7-bis(2- isopropoxyethoxy)quinazolin-4(3H)—one AO/Vo N N\ \' The title nd was isolated using the process described for Example 113 as a white solid. Yield: 124 mg (27%). MP 124-125°C. 1H NMR (400 MHz, CDCI3): 510.04 (br s, 1H), 7.60 (s, 2H), 6.85 (d, J = 2.34 Hz, 1H), 6.63 (d, J = 2.34 Hz, 1H), 4.23 (t, J = 4.88 Hz, 4H), 3.85 (dt, J = 10.54 and 5.27 Hz, 4H), 3.80 - 3.64 (m, 2H), 2.64 (s, 6H), 1.23 (d, J = 6.24 Hz, 6H), 1.17 (d, J = 6.24 Hz, 6H). MS (ES+) m/z: 456.17 (100%).

Example 115. Preparation of 7-(2-(Benzyloxy)ethoxy)-2~(2,6-dimethylpyridiny|)— -methoxyquinazolin—4(3H)—one O/\/O N\ \ To a suspension of 2,6-dimethyl-pyridinyl)—methanol (6.00 g, 0.043 mol) in acetonitrile (150 mL), 1,2—benziodexol-3(1H)—onehydroxyoxide (IBX) (14.8 9, 0.0503 mol) was added and the reaction mixture was refluxed for 2 hours. The solid was filtered off and washed with acetonitrile. The filtrate was evaporated in vacuo to give 2,6—dimethyl-pyridinecarbaldehyde as a brown liquid. Yield: 4.30 g (72.7%).

To a stirred solution of 2-amino—4,6-difluoro-benzamide (4.00 9, 0.0237 mol) and 2,6—dimethyI-pyridine—4-carbaldehyde (3.20 9, 0.0237 mol) in N,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt%, 5.05 9, 0.0284 mol), and ene sulfonic acid monohydrate (0.90 g, 4.74 mmol) were added and the reaction mixture was stirred at 130 °C for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered to give 2-(2,6—dimethyI-pyridinyl)-5,7—difluoro-3H—quinazolinone as a yellow solid, which was used in the next step without further purification. Yield: 3.70 g (54.3%).

To a suspension of 2-(2,6—dimethyl-pyridin—4-yl)—5,7—difluoro-3H— quinazolinone (2.70 g, 9.4 mmol) in DMF (15 mL), a solution of sodium methoxide in methanol (25 wt%, 6.0 g, 28.2 mmol) was added and the reaction mixture was d at room temperature for 16 h. Water was added, acidified to pH imately 4-5 with acetic acid and the precipitated solid was filtered and dried under vacuum to give crude —dimethyl-pyridiny|)—7-f|uoro-5—methoxy- 3H-quinazolinone (2.40 g), which was further purified by column tography (silica gel 230—400 mesh; eluting with 2% methanol solution in romethane) to yield pure compound as a light yellow solid. Yield: 0.35 g (12.4%).

To a solution of 2—benzyloxy-ethanol (1.15 g, 10.0 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.20 g, 5.0 mmol) was added in ns and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2—(2,6-dimethyl- pyridinyl)fluoro-5—methoxy-3H—quinazolinone (0.30 g, 1.0 mmol) and the reaction mixture was stirred at 85 °C for 24 hours. Water was added, and the mixture was acidified to pH imately 4-5 with acetic acid and the precipitated solid was filtered to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; eluting with hexane and ethyl acetate :1) to obtain the title compound as a white solid. Yield: 0.140 g (32.4%). MP 178-180°C. MS (ES) m/z: 432.18 (M++1). 1H NMR (400 MHz, : (s, 1H), 7.69 (s, 2H), 7.29—7.40 (m, 5H), 6.85 (d, J = 2.0 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 4.66 (s, 2H), 4.29 (m, 2H), 3.97 (s, 3H), 3.89 (m, 2H), 2.66 (s, 6H).

Example 116. Preparation of 2-(2,6-Dimethylpyridin—4-yl)—6-(2- morpholinoethyl)quinazolin-4(3H)-one y/\N/\/ MP 248.5-249.3°C. 1H NMR (400 MHz, CDCI3): 611.6 (s, 1H), 8.18 (s, 1H), 7.87—7.76 (m, 3H), 7.76-7.65 (m, 1H), 3.76 (t, J = 4.49 Hz, 4H), 2.99 (t, J = 8.01 Hz, 4H), 2.71 (s, 6H), 2.75-2.65 (m, 2H), 2.56 (br s, 4H). MS (ES+) m/z: 363.16 (M+1).

Example 117. Preparation of 2-(2-methylpyridin—4-yl)—6- olinomethyl)quinazolln—4(3H)—one N / O \ A solution of n-butyllithium (1.6 M solution in hexanes, 6.32 mL, 12.6 mmol) in THF (50 mL) was cooled to ~78 °C. A solution of 4-bromomethyl- pyridine (2.00 g, 11.6 mmol.) in anhydrous THF (5 mL) was added. The resulting e was stirred for 5 minutes, then anhydrous N,N dimethylformamide (3.39 g, 46.4 mmol,) was added. The solution was stirred for 90 min at -78 °C and quenched with saturated aqueous NH4Cl on (30 mL). The reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (3X100 mL), and the combined organic phase was washed with brine (100 mL) and dried over anyhdrous Na2804. The solvent was evaporated under reduced pressure to give 2-methyl-pyridinecarbaldehyde. Yield: 1.209, (85%).

To a solution of 2-aminomorpholinylmethyl-benzamide (0.58 g, 2.4 mmol) and 2—methyl-pyridinecarbaldehyde (0.3 g, 2.4 mmol) in MN- dimethylacetamide (10 mL) were added NaHSO3 (58.5 wt%, 0.48 g, 2.7 mmol) and p-TSA (0.23 g, 1.2 mmol) and the reaction mixture was heated at 115 °C for 16 hours, and the solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with 4% methanolic ammonia in dichloromethane) to give the title compound as a white solid. Yield: 0.18 g (22%). MP 267—268°C. 1H NMR (400 MHz, e): 611.74 (br s, 1H), 8.77 (d, J = 5.4 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.94-7.83 (m, 3H), 3.75(t, J = 4.2 Hz, 4H), 3.74 (s, 2H), 2.77 (s, 6H), 2.53—2.46 (m, 4H). MS (ES+) m/z: 337.41 (M+1). e 118. Preparation of oxy(2-methoxyethoxy)(2~methylpyridin- 4~yl)quinazolin—4(3H)-one To a solution of 2—amino-4,6-difluoro-benzamide (0.71 g, 4.10 mmol) and 2-methyl—pyridinecarbaldehyde (0.50 g, 4.10 mmol) in MN— ylacetamide (10 mL) were added NaHSO3 (58.5 wt%, 1.00 g, 5.70 mmol) and p-TSA (0.16. g, 0.08 mmol). The reaction mixture was heated at 115 °C for 30 hours, then cooled to room temperature. The solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane) to afford 5,7-difluoro(2— methyl-pyridinyl)—3H—quinazolinone as a light yellow solid. Yield: 0.30 g (26%).

To a suspension of 5,7—difluoro(2-methyI-pyridinyl)~3H— quinazolin-4—one (0.30 g, 1.09 mmol) in anhydrous DMF (8 mL) was added a solution of sodium methoxide in methanol (25 wt%, 0.59 g, 10.9 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Water was added, the mixture was ied to pH approximately 5 with acetic acid, and the precipitated solid was filtered and dried under vacuum to give ro-5—methoxy— 2-(2-methyl-pyridinyl)—3H—quinazolin—4-one as a light yellow solid. Yield: 0.24 g (76%).

To a solution of 2—methoxy~ethano| (0.64 g, 8.40 mmol) in anhydrous DMSO (4 mL) was added sodium hydride (60% suspension in mineral oil, 0.12 g, .00 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of 7—fluoro-5— methoxy—2-(2-methyl-pyridinyl)—3H—quinazolin—4-one (0.24 g, 0.84 mmol) in anhydrous DMSO (12 mL). The reaction mixture was stirred at 80 °C for 3 hours, then cooled to room temperature, and diluted with ether (500 mL). The solid was filtered and washed with ether. The crude compound was purified by column tography (silica gel 0 mesh; 4% methanol in dichloromethane). The compound was further ed by ative HPLC to give the title compound as a white solid. Yield: 60 mg (21%). MP 260—262°C. 1H NMR (400 MHz, DMSO-d6): 6 8.62 (d, J = 5.07 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J = 5.07 Hz, 1H), 6.80 (d, J = 2.34 Hz, 1H), 6.61 (d, J = 2.34 Hz, 1H), 4.25 (t, J = 4.68 Hz, 2H), 3.86 (s, 3H), 3.71 (t, J = 3.90 Hz, 2H), 3.33 (s, 3H), 2.57 (s, 3H). MS (ES) m/z: 342.07 (M+1) (100%).

Example 119. Preparation of 2-(2,6-Dimethylpyridinyl)—6—(2—(pyrrolidin yl)ethy|)quinazolin—4(3H)-one @"Q/YNHN / To a suspension of 1H-benzotriazole (10.0 g, 83.9 mmol) in water (84 mL) was added pyrrolidine 2 (6.3 mL, 226.6 mmol). After 10 minutes of vigorous stirring at room temperature, formaldehyde 37% aqueous solution was added. The reaction mixture was stirred for 1 hour, then the precipitate was filtered off, and washed with water to afford 1-pyrrolidinylmethyI-1H- benzoimidazole as an off-white solid. Yield: 14.58 g ).

To a mixture of zinc powder (1.05 g, 16.05 mmol) and 1—pyrrolidin ylmethyl—1H-benzoimidazole (2.95 g, 14.59 mmol) in N,N-dimethy| formamide (40 mL) under a nitrogen atmosphere was added 5—bromomethylnitro-benzoic acid methyl ester (4.0 g, 14.59 mmol). The reaction mixture was stirred at room temperature for 24 hours, then quenched at 0 °C with an ld 25% aqueous solution of ammonium hydroxide (108 mL). The stirring was continued until most of the solid had dissolved. Undissolved solid was ed off and the te was extracted with diethyl ether. The combined organic layers were washed with 1 N aqueous sodium hydroxide, then water, and were dried over anhydrous sodium sulfate and concentrated under high vacuum to give 2-nitro(2—pyrrolidin-1—y|- ethyl)—benzoic acid methyl ester as an orange oil. Yield: 1.3 g (32%). The crude material was used for the next step without further purification.

To a solution of 2—nitro(2-pyrrolidinyl-ethyl)—benzoic acid methyl ester in THF (16 mL) was added 10% palladium on al (0.23 g). The resulting on mixture was enated under 40 psi for 2 hours, then the catalyst was filtered off and the filtrate concentrated under high vacuum to give 2- amino(2~pyrrolidin-1—yl-ethyI)-benzoic acid methyl ester as a yellow oil. Yield: 1.04 g (89.6 %). The crude material was used in the next step without r purification.

To a solution of 2—amino(2-pyrrolidin—1-yl-ethyl)—benzoic acid methyl ester (1.04 g, 4.19 mmol) in a mixture of THF (8 mL) and methanol (5 mL) was added lithium hydroxide (0.36 9), followed by water (3 mL). The reaction mixture was stirred at room ature overnight, and then refluxed for 4 hours.

After cooling to room temperature, the was solvent concentrated. The pH was adjusted to imatley 5 with 2 N aqueous hydrochloric acid and the residue was evaporated to dryness to give 2-amino—5-(2-pyrrolidin-1—yl—ethyl)—benzoic acid as a chloride salt. Yield: 1.84 g. The crude material was used in the next step without further purification.

To a on of 2-amino(2-pyrrolidin—1-yl-ethyl)—benzoic acid (0.41 g, 1.75 mmol) in a mixture of THF (5.1 mL) and N,N—dimethyl formamide (1.75 mL) was added EDCI (0.84 g, 4.37 mmol), followed by HOBt (0.71 mL, 5.25 mmol). The reaction mixture was stirred for 30 minutes. Then, N-methyl line (0.67 mL, 6.12 mmol) was added, followed by 50% aqueous ammonium hydroxide (1.2 mL, 17.5 mmol). The resulting mixture was stirred at room temperature for 24 hours. Then, the solvent was reduced and the residue was extracted with methylene chloride. The combined organic layers were washed with brine, water, and dried over sodium sulfate. After solvent evaporation under high vacuum, the crude orange oil (0.72 g) was purified by column chromatography (silica gel 0 mesh; 5/95 methylene chloride/7 N ammonia in MeOH as eluent) to give pure 2—amino(2—pyrrolidin—1-yl-ethyl)—benzamide as a light yellow s oil. Yield: 0.16 g (39.2%).

To a solution of 2-amino-5—(2-pyrrolidin-1—yl-ethyl)-benzamide (0.16 g, 0.69 mmol) in N,N-dimethyl acetamide (7 mL) under a nitrogen atmosphere was added 2,6-dimethyl—pyridine-4—carbaldehyde (0.09 g, 0.68 mmol), followed by sodium hydrogensulfite (0.14 g, 1.36 mmol) and enesulfonic acid (0.32 g, 1.7 mmol). The resulting mixture was heated at 120 °C overnight. Then, the solvent was removed under reduced pressure, the e was diluted with ethyl acetate, and was extracted with water. The pH of the water layer was made basic by adding sodium bicarbonate, then the layer was extracted with methylene chloride, dried over anhydroussodium sulfate, and was evaporated under high vacuum. The crude yellow solid (0.09 g) was purified by column chromatography (silica gel 230—400 mesh; 95/5 ene chloride/MeOH as eluent) to afford the title compound as a yellow solid. Yield: 54 mg (23%). MP 212.3—213.2°C. 1H NMR (400 MHz, CDCI3): 6 8.19 (s, 1H), 8.19 (br s, 1H), 7.83-7.77 (m, 1H), 7.76—7.70 (m, 3H), 30-315 (m, 2H), 2.78-2.88 (m, 2H), 2.7 (s, 6H), 2.58-2.68 (m, 4H), 1.8— 1.95 (m, 4H). MS (ES+) m/z: 347.11 (M+1).

Example 120. Preparation of 2—(2,6—Dimethylpyridin—4-yl)(2-methoxyethoxy)—5- (2-(pyrrolidin—1-yl)ethoxy)quinazolin—4(3H)-one To a solution of 2—pyrrolidiny|—ethanol (5.09 g, 44.2 mmol) in DMF (10 mL) was added sodium e (60% suspension in l oil, 0.88 g, 22.1 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this e was added 2-(2,6-dimethyl-pyridiny|)-5,7- difluoro-3H-quinazolinone (0.63 g, 2.21 mmol) and the on mixture was stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was neutralized to pH approximately 6 with acetic acid. Solvent was evaporated, the residue was ved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. Crude compound was purified by the Simpliflash system (0—4% methanol in CH2C|2 as eluent) to afford 2-(2,6-dimethyl-pyridin—4-y|)f|uoro—5-(2-pyrrolidinyl-ethoxy)-3H—quinazolin~4— one as a yellow solid. Yield: 0.61 g (72%).

To a solution of 2—methoxy—ethanol (1.35 g, 17.8 mmol) in DMF (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.36 g, 8.89 mmol) in small portions and the reaction mixture was stirred at room ature for 30 minutes. To this mixture was added 2-(2,6-dimethyl-pyridin—4-yl)—7-fluoro-5— (2-pyrrolidin—1~yl—ethoxy)-3H—quinazolin-4~one (0.34 g, 0.89 mmol) and the reaction mixture was stirred at 70-80°C for 16 h, then cooled to room temperature.

Water (10 mL) was added, and the mixture was neutralized to pH approximatley 6 with acetic acid. Solvent was evaporated; the residue was purified by the Simpliflash system (2-5% 7.0M ammonia in methanol and CH2C|2 as ). The compound was further purified by preparative HPLC to give the title compound as a yellow solid. Yield: 72 mg (18%). MP 60.4-62.3°C. 1H NMR (400 MHz, CDCI3): 5 .23 (br s, 1H), 8.50 (br s, 1H), 7.60 (s, 2H), 6.76 (br s, 1H), 6.43 (br s, 1H), 4.35 (m., 2H), 4.21 (m, 2H), 3.79 (s, 3H), 3.47- 3.38 (m, 6H), 2.64 (s, 6H), 1.99 (m, 4H).

MS (ES) m/z: 437.09 (M-1) (100%).

Example 121. ation of 2-Hydroxyethoxy)phenyl)—5,7- dimethoxyquinazolin—4(3H)—one /O NYQO/VOH /0 o To a suspension of sodium hydride (0.426 g, 10.7 mmol) in DMF (30 mL) at room temperature was added 3-hydroxybenzaldehyde (1.00 g, 8.20 mmol).

The ing suspension was stirred at room temperature for 1 hour and (2- bromo-ethoxy)—tert—butyl-dimethyl-silane (4.4 mL, 20.5 mmol), was then added.

The resulting mixture was stirred at 60 °C under nitrogen for 14 hours, cooled to room temperature, d with water (100 mL), extracted with ethyl acetate (250 mL), and concentrated. The crude product was purified by column chromatography (SiOz, hexane /ethyl acetate = 4:1) to afford 3—[2-(tert-butyl- dimethyl—siIanyloxy)-ethoxy]-benzaldehyde. lt was re-dissolved in THF (50 mL), mixed with 1 N tetra-n-butylammonium fluoride in THF (15 mL), and stirred at room temperature for 8 h. The reaction mixture was then concentrated and the e was purified by column chromatography (SiOz, hexane /ethyl acetate = 4:1) to afford 3-(2-hydroxy-ethoxy)—benzaldehyde as a colorless oil. Yield: 0.68 g (50% for two steps).

A mixture of 2—amino—4,6—dimethoxy-benzamide (195 mg, 1.00 mmol), 3-(2-hydroxy—ethoxy)—benzaldehyde (166 mg, 1.00 mmol), p- toluenesulfonic acid monohydrate (38 mg, 0.20 mmol), and sodium bisulfite (264 mg, 1.50 mmol) in N,N—dimethylacetamide (10 mL) was stirred at 130 °C under nitrogen for 14 hours, cooled to room temperature, and diluted with 0.2 N potassium ate aqueous solution (50 mL). It was extracted with ethyl acetate (250 mL), dried over sodium sulfate, and concentrated. The solid e was re- dissolved in dichloromethane (5 mL), and precipitated with ethyl acetate (15 mL) and hexanes (50 mL). it was filtered and washed with hexanes to afford the title compound as a yellow solid. Yield: 70 mg (20%). MP 246.0°C. 1H NMR (400 MHz, CDCl3)16 7.64 (d, 1H), 7.60 (d, 1H), 7.45 (t, 1H), 7.12 (dd, 1H), 6.84 (d, 1H), 6.48 (d, 1H), 4.21 (t, 2H), 4.03 (t, 2H), 3.99 (s, 3H), 3.94 (s, 3H). MS (ES+) m/z: 343.55 (M+1).

Example 122. ation of 2-(3-(2—Hydroxyethoxy)—5-methylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one /o N\ O/\/OH /0 o To a solution of 3,5-dimethyl-phenol (3.000 g, 24.55 mmol) in MN— dimethylformamide (120 mL) under nitrogen were added potassium carbonate (16.96 9, 122.7 mmol) and (2—bromoethoxy)—tert—butyldimethylsilane (7.90 mL, 36.8 mmol). The resulting slurry was heated at reflux for 20 hours; then, the solvent was removed under high vacuum. The residue was dissolved in ethyl acetate and the solution was backwashed with 0.2 N aqueous sodium hydroxide, water, and then brine, dried over sodium sulfate, and concentrated. The crude material (5.69 g) was ed by column chromatography (silica gel 230-400 mesh; methylene de as eluent) to give tert—butyl-[Z-(3,5-dimethyl-phenoxy)— ethoxy]-dimethylsilane as light yellow oil. Yield: 3.72 g (47%).

To a solution of tert-butyl-[2—(3,5—dimethyl-phenoxy)-ethoxy]- dimethylsilane (2.22 g, 7.91 mmol) in carbon tetrachloride (50 mL) under nitrogen was added N-bromosuccinimide (1.57 g, 8.70 mmol) and benzoyl peroxide (0.38 g, 1.58 mmol). The resulting mixture was heated at reflux for 3 hours with simultaneous illumination by a sun lamp. The precipitate was filtered off and the filtrate was concentrated under d pressure. The crude material (3.999) was purified by column chromatography (silica gel 230-400 mesh; 1/0 to 4/1 hexanes/ EtOAc as eluent) to give [2-(3-bromomethyl—5—methyl~phenoxy)-ethoxy]-tert—butyl- dimethyl—silane as a light yellow oil. Yield: 2.17 g (75%).

To a solution of [2-(3—bromomethylmethyl—phenoxy)-ethoxy]-ten‘— butyl-dimethyl-silane (2.17 g, 6.04 mmol) under nitrogen in 2-nitopropane (2.0 mL, mmol) was added sodium ethoxide (0.620 g, 9.06 mmol). The resulting mixture was heated at 90 °C for 15 hours, and was then diluted with ethyl acetate and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were shed with water and brine, dried over sodium e, and concentrated. The crude material (1.81 g) was purified by column chromatography (silica gel 230-400 mesh; 1/0 to 4/1 hexanes / EtOAc as eluent) to give 3-[2-(tert—butyl—dimethyl- loxy)—ethoxy]—5-methyl-benzaldehyde as a yellow oil. Yield: 0.97 g (55%).

To a solution of 2—amino-4,6-dimethoxy-benzamide (0.350 g, 1.78 mmol) in N,N-dimethylacetamide (20 mL) under nitrogen was added 3-[2-(tert— butyl-dimethyl—silanyloxy)-ethoxy]-5—methyl~benzaldehyde (0.520 g, 1.78 mmol) ed by sodium ensulfite (0.270 g, 2.67 mmol), and p—toluenesulfonic acid (0.033 g, 0.18 mmol). The ing mixture was heated at 120 °C for 24 hours, then the solvent was concentrated to 5 mL under reduced pressure, and water was added to obtain a precipitate, which was filtered off and washed with EtZO and methylene chloride. The resulting solid was dissolved in hot CH2Cl2/ MeOH, and then precipitated by adding 320, and purified by preparative thin- layer chromatography (DC~Fertigp|atten SlL G—100 UV, 9/1 methylene chloride/ MeOH as eluent) to give the title compound as a yellow solid. Yield: 81 mg (13%).

MP 106.9-109.1°C. 1H NMR (400 MHz, CDCl3): 57.86 (s, 1H), 7.41 (d, 2H), 6.82 (s, 1H), 6.57 (s, 1H), 4.15-4.13 (m, 2H), .90 (m, 8H), 2.43 (s, 3H). MS (ES+) m/z: 357.53 (M+1).

Example 123. Preparation of 5,7-Dimethoxy(3—methoxy-5—(2-(pyrrolidin~1- yl)ethoxy)phenyl)quinazolin-4(3H)-one /0 o To a 1.0—L three-neck flask was added sodium ethanethiolate (80%, 28.5 g, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to 145° C for 1.5 hours. Then, 3,5-dimethoxy-benzaldehyde (15.0 g, 90.0 mmol) in anhydrous DMF (350 mL) was added over a period of 8 s. The reaction was kept at 145 °C for another 1 hour, then cooled to room temperature.

Saturated sodium chloride solution (2.5 L) and formaline (37%, 240 mL) together with acetic acid (500 mL) was added. The resulting on was thoroughly extracted with ethyl acetate, the c phase was dried with sodium sulfate, and the solvent was removed under vacuum. The crude compound was purified by column chromatography (silica gel 230~400 mesh; eluting with dichloromethane and ethyl acetate 7:1) to give 3—hydroxymethoxy-benzaIdehyde as a white solid. Yield: 12.0 g (88%). 3-Hydroxy—5-methoxy-benzaldehyde (12.0 g, 78.9 mmol) and [1 ,3]dioxolan—2-one (13.9 9, 157.0 mmol) in anhydrous DMF (50 mL) was added potassium carbonate (21.6 9, 157.0 mmol). The mixture was then heated to 110 °C for 16 hours. The reaction mixture was cooled to room temperature. Solid potassium carbonate was filtered and washed with ethyl acetate. The organic phase was collected and solvent was removed. The e was purified by column chromatography (silica gel 230—400 mesh; eluting with romethane and ethyl acetate 7:1), to give ydroxy—ethoxy)methoxy-benzaldehyde as a brown liquid. Yield: 10.0 g (65%).

To a solution of 2—amino-4,6-dimethoxy—benzamide (7.50 g, 38.2 mmol) and 3-(2—hydroxy-ethoxy)methoxy—benzaldehyde (7.50 g, 38.2 mmol) in N,N-dimethylacetamide (30 mL) was added NaH803 (58.5 wt%, 4.37 g, 42.0 mmol) and p‘TSA (0.72 g, 3.8 mmol). The reaction mixture was heated to 115—120 °C for 16 hours, and then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with water (50 mL), and the solid was filtered, collected, and mixed with ether (50 mL), then filtered and dried under vacuum, to give 2-[3—(2-hydroxy—ethoxy)—5—methoxy-phenyl]—5,7— dimethoxy—3H—quinazolin~4-one as a white solid. Yield: 10 g (70%).

To a solution of 2-hydroxy-ethoxy)—5—methoxy-phenyl]—5,7- dimethoxy-3H—quinazolinone (8.00 g, 21.5 mmol) in anhydrous DMF (30 mL) was added carbon romide (9.80 g, 29.5 mmol) and triphenylphosphine (7.78 g, 29.5 mmol). The reaction mixture was stirred at 40 °C for 7 hours. DMF was removed under vacuum and romethane (200 mL) was added. The organic phase was washed with water (150 mL), brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was removed and the residue was washed three times with a mixture of ether and dichloromethane (20:1, 200 mL) to give 2- bromo-ethoxy)—5-methoxy-phenyl]-5,7-dimethoxy-3H—quinazolin-4—one (5) as a white solid. Yield: 8.9 g (95%).

To a solution of 2-[3-(2-bromo—ethoxy)methoxy-phenyl]—5,7— dimethoxy—3H—quinazolinone (7.10 g, 16.0 mmol) in THF (20 mL) was added pyrrolidine (11.38 9, 160.0 mmol) and the reaction mixture was stirred at room temperature for 15 hours. THF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 230—400 mesh; eluting with 5% 2.0 M a in methanol solution in dichloromethane) to give the title compound as a white solid. Yield: 3.2 g (47 %). MP 159-160°C. 1H NMR (400 MHz, CDCI3)I 610.66 (s, 1H), 7.25 (m, 2H), 6.84 (d, J = 2.0 Hz, 1H), 6.67 (t, J = 2.4 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 2.93 (t, J = 6.0 Hz, 2H), 2.64 (m, 4H), 1.80 (m, 4H). MS (ES+) m/z: 426.20 (M+1).

Example 124. Preparation of N-(2-(3—(5,7—dimethoxyoxo-3,4—dihydroquinazolin- 2-yl)methoxyphenoxy)ethyl)acetamide /O N\ O/\/N\"/ NH O To a 1.0-L three-neck flask was added sodium ethanethiolate (80%, 28.5 9, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to 145 °C for 1.5 hours; then, a solution of 3,5-dimethoxy-benzaldehyde (15.0 g, 90.0 mmol) in ous DMF (350 mL) was added over a period of 8 minutes.

The reaction was kept at 145 °C for 1 hour, then cooled to room temperature.

Saturated sodium de solution (2.5 L) and formaline (37%, 240 mL), together with acetic acid (500 mL), was added. The resulting on was thoroughly extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Solvent was removed under vacuum, and the crude compound was purified by column chromatography (silica gel 230—400 mesh; eluting with 7:1 dichloromethane and ethyl e) to give 3~hydroxy—5-methoxy-benzaldehyde as a white solid. Yield: 12.0 g (88%).

To a solution of 3—hydroxy—5-methoxy—benzaldehyde (12.0 g, 78.9 mmol) in anhydrous DMF (50 mL) was added [1 ,3]dioxolanone (13.9 g 157.0 mmol) and potassium carbonate (21.6 g, 1570 mmol). The on e was then heated to 110 °C for 16 hours, then cooled to room temperature. Solid ium carbonate was filtered and washed with ethyl acetate. The organic phase was collected and solvent was removed. The e was purified by column chromatography (silica gel 230—400 mesh; eluting with 7:1 dichloromethane and ethyl acetate) to give 3-(2-hydroxy-ethoxy)-5—methoxy- benzaldehyde as a brown . Yield: 10.0 g (65%).

To a solution of 2—amino—4,6—dimethoxy-benzamide (7.50 g, 38.2 mmol) and 3—(2-hydroxy—ethoxy)—5-methoxy—benzaIdehyde (7.50 g, 38.2 mmol) in N,N-dimethylacetamide (30 mL) were added NaH803 (58.5 wt%, 4.37 g, 42.0 mmol) and p-TSA (0.72 g, 3.8 mmol). The reaction mixture was heated to 115—120 °C for 16 hours, and then cooled to room temperature. N,N—dimethylacetamide was removed under reduced pressure, the residue was diluted with water (50 mL), and the solid was filtered, collected and mixed with ether (50 mL), ed, and dried under vacuum, to give 2-[3-(2—hydroxy-ethoxy)—5-methoxy-phenyl]-5,7- climethoxy-3H-quinazolinone as a white solid. Yield: 10 g (70%).

To a solution of 2-[3—(2-hydroxy—ethoxy)—5-methoxy~phenyl]—5,7- dimethoxy—3H—quinazollnone ( 8.00 g, 21.5 mmol) in anhydrous DMF (30 mL) was added carbon tetrabromide (9.80 g, 29.5 mmol) and triphenylphosphine (7.78 g, 29.5 mmol). The reaction mixture was stirred at 40 °C for 7 hours. DMF was removed under vacuum and romethane (200 mL) was added. The organic phase was washed with water (150 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was removed and the residue was washed three times with a mixture of ether and dichloromethane (20:1, 200 mL) to give 2— [3—(2-bromo-ethoxy)—5-methoxy-phenyl]-5,7-dimethoxy-3H—quinazolin—4-one as a white solid. Yield: 8.9 g (95%).

To a solution of 2-[3-(2-bromo—ethoxy)methoxy—phenyl]-5,7— dimethoxy-3H—quinazolin—4—one (0.37 g, 0.84 mmol) in DMF (10 mL) was added sodium azide (0.14 g, 2.11 mmol) and the reaction mixture was stirred at 70 °C for 7 hours. DMF was removed under reduced pressure and dichloromethane (100 mL) was added. The organic phase was washed with water (50 mL), then brine (50 mL), and dried over anhydrous sodium sulfate. Solvent was d and the residue was purified by column chromatography (silica gel 230-400 mesh; 30—40% ethyl acetate in dichloromethane as eluent) to give a white solid. Yield: 0.23 g (69 2-[3-(2-Azido—ethoxy)—5—methoxy-phenyl]-5,7-dimethoxy-3H— quinazolin-4—one (90 mg, 0.22 mmol) was taken in thioacetic acid (2 mL) and the reaction e was d at room temperature for 2 hours. Thioacetic acid was removed under reduced pressure, and the residue was ed by column chromatography (silica gel 230-400 mesh; 3.5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 45 mg (49%). MP 264— 265°C. 1H NMR (400 MHz, DMSO—d6)2812.05(s, 1H), 8.13 (t, J = 5.86 Hz, 1H), 7.39 (d, J = 1.56 Hz, 2H), 6.76 (d, J = 2.34 Hz, 1H), 6.69 (t, J = 2.15 Hz, 1H), 6.55 (d, J = 2.34 Hz, 1H), 4.07 (t, J = 5.67 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.43 (q, J = 5.47 Hz, 2H), 1.84 (s, 3H). MS (ES+) m/z: 414.11 (M+1).

Example 125. Preparation of 2-(3,5—Dimethoxyphenyl)—6—(pyridin o)quinazolin-4(3H)—one To a mixture of 2-amino—5-nitro—benzoic acid (12.9 g, 81.9 mmol), 1-ethyl(3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (17.3 g, 90.1 mmol), 1—hydroxybenzotriazole hydrate (HOBt) (12.2 g, 90.1 mmol) in THF (200 mL) was added 4-methylmorpholine (NMM) (9.91 mL, 90.1 mmol). After minutes, ammonium hydroxide (50% WV, 50 mL) was added. The mixture was stirred at room temperature under nitrogen for 17 hours. Solvent was removed under d pressure. Water was added. The solid separated was filtered, washed with aqueous NaHCO3 solution, and with water, and dried in air, to afford 2—amino—5-nitro—benzamide as a yellow solid. Yield: 9.88 g (66%).

A mixture of 2-amino—5-nitro-benzamide (1.81 g, 10.0 mmol), 3,5-dimethoxy—benzaldehyde (1.83 g, 11.0 mmol), sodium hydrogen sulfite (58.5 wt%, 3.94 g, 22.0 mmol), and p—toluenesulfonic acid monohydrate (0.38 g, 2.00 mmol) in N,N-dimethylacetamide (20 mL) was stirred at 150 °C for 17 hours under nitrogen and then cooled to room temperature. Saturated aqueous NaHCO3 (approximately 1 mL) was added. The mixture was stirred at room temperature for 2 hours, then trated to dryness. Water (80 mL) was added, stirred for 0.5 hours, and filtered. The solid was air dried. The crude compound was purified by column chromatography (silica gel 230-400 mesh; ethyl acetate as eluent) to give 6—amino(3,5~dimethoxy—phenyl)—3H—quinazolinone as a yellow solid. Yield: 1.50 g (50%). 6-Amino—2—(3,5-dimethoxy-phenyl)—3H—quinazolinone (297 mg, 1.00 mmol), 4-bromopyridine hydrochloride (194 mg, 1.00 mmol), tris(dibenzyldieneacetone)dipalladium(0) (18 mg, 0.02 mmol), 1,1’—bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol), sodium utoxide (230 mg, 2.40 mmol) and pyridine (3 mL) were heated at 140 °C in microwave oven (150 W) for 1 hour. The mixture was concentrated under vacuum to dryness.

The residue was ed by column tography (silica gel 230-400 mesh; 5% methanol in dichloromethane and then 10% 2 N NH3 in methanol and dichloromethane as eluent) to give the title compound as a brown/beige solid.

Yield: 176 mg (47%). MP 289-290°C. 1H NMR (400 MHz, DMSO—de): 6 9.24 (s, 1H), 8.29 (d, J = 5.6 Hz, 2H), 7.90 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.38 (s, 2H), 7.03 (d, J: 5.2 Hz, 2H), 6.69 (s, 1H), 3.85 (s, 6H). MS (ES+) m/z: 375.13 (M+1). e 126. ation of 5,7-Dimethoxy—2—(3-methoxyphenyl)quinazolin- 4(3H)-one A mixture of 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), 3-methoxybenzaldehyde (0.306 mmol), NaH803 (94%, 0.0474 g, 0.428 mmol), and p—TsOH-HZO (0.0175 9, 0.0918 mmol) in DMA (3.06 mL) was heated at 140 °C for 20 hours. The mixture was diluted with EtOAc (300 mL), washed with water (3X75 mL), then brine (75 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified on silica gel (40 g, CHgClgl MeOH) and the product was freeze-dried from MeCN/HZO to provide the title compound (69%) as an off-white solid. 1H NMR (300 MHz, DMSO-ds): 8 12.04 (s, 1H), 7.82—7.70 (m, 2H), 7.43 (t, J = 7.98 Hz, 1H), 7.13 (dd, J = 8.19, 2.46 Hz, 1H), 6.76 (d, J = 2.19 Hz, 1H), 6.55 (d, J = 2.19 Hz, 1H), 3.92—3.82 (m, 9H); MS (APCl) m/z 313 [C17H15N204+H]+.

Example 127. Quantification of hlL-6 mRNA In this example, hlL-6 mRNA in tissue culture cells was quantitated to e the transcriptional tion of hlL—6 when treated with a compound of the invention.

A human leukemic monocyte lymphoma cell line (U937) was plated (3.2><105 cells per well) in a 96-well plate in 100 pL RPMl-1640, and differentiated for 3 days prior to the addition of the compound of st. The cells were pretreated for 1 h with the test compound prior to stimulation with saccharide from ichia coli. The cells were incubated at 37°C for 3 h before the cells were harvested. At time of harvest, the spent media was removed from the cells and the cells were rinsed in 200 pL PBS. Cell lysis solution (70 pL) was added the cells in each well and incubated for 5—10 min at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the "mRNA Catcher PLUS plate" (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. Elution buffer (E3, 70 pL) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 min at 68°C and then immediately placing the plate on ice.

The eluted mRNA isolated was then used in a one—step tative real-time PCR reaction, using components of the Ultra Sense Kit together with Applied Biosystems -probe mixes. ime PCR data was analyzed, normalizing the Ct values for hlL—6 to an internal l, prior to ining the fold induction of each unknown sample, relative to the control.

In Table 2, an active compound is one that causes a 2 20% inhibition in lL-6 mRNA at a concentration less than or equal to 10 uM.

Table 2.

Inhibition of lL—6 Example expression ,7—dimethoxy—2—(4—morpholinophenyl)quinazolin-4(3H)-one Active 2—(4—((3R,53)—4—acetyl-3,5-dimethylpiperazinyl)phenyI)-5,7- dimethoxypyridolz,3-d]pyrimidin—4(3H)—one Active 2-(4-(4-hydroxypiperidinyl)phenyl)—5,7-dimethoxypyrido[2,3-d]pyrimidin— 4(3H)—one Active 2-(4—((3R,5S)acetyl—3,5—dimethylpiperazinyl)phenyl)-5—methoxy(2- methoxyethoxy)quinazolin-4(3H)~one Active 4-isopropylpiperazinyl)phenyl)—5,7-dimethoxyquinazolin-4(3H)-one Active 2-(4-(4-acetylpiperazinyl)phenyl)—5,7-dimethoxyquinazolin-4(3H)—one ' 5,7—dimethoxy(4—(piperazinyl)phenyl)quinazolin-4(3H)—one 4-(5,7—dimethoxyoxo—3,4—dihydroquinazolinyl)phenyl)piperidin—4- yl)acetamide N-(1-(4-(5,7—dimethoxy—4-oxo-3,4-dihydroquinazolin—2-yl)phenyl)piperidin yl)methanesulfonamide 3—(1—(4—(5,7-dimethoxy—4—oxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)—1,1-dimethylurea Active I 2—(4—(4-hexanoylpiperazin—1-yl)phenyl)—5,7-dimethoxyquinazolin-4(3H)—one Active 2-(4-(4-isobutyrylpiperazin—1—yl)phenyl)—5,7—dimethoxyquinazolin—4(3H)-one 2-(4-(4-benzoylpiperaziny|)phenyl)-5,7-dimethoxyquinazolin-4(3H)—one 2-(4—(4-(4-fluorobenzoyl)piperazin—1—yl)phenyl)—5,7—dimethoxyquinazolin- 4(3H)—one N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)pheny|)piperidin yl)benzamide , 7--dimethoxy——2--(—4(4—picolinoylpiperazin—1——yl)phenyl)quinazolin-4((3H)one Active , 7——dimethoxy--(4—(4—nicotinoylpiperazin—1——yl)phenyl)quinazolin-4(3H)—one I Active 2--(4—(4-isonicotinoylpiperazin--yl)phenyl)-5, 7——dimethoxyquinazolin-4(3H)- one 1 Active ,7-dimethoxy—2—(4-(4-(thiophene-2—carbonyl)piperazin—1— yl)phenyl)quinazolin-4(3H)—one Active 2—(4—(4-(5-chioromethyI-1H—pyrazoIecarbonyl)piperaziny|)phenyl)— ,7-dimethoxyquinazolin—4(3H)—one Active methoxy-Z-(4—(4—(3,3,3—trifluoropropanoyl)piperazin y|)phenyl)quinazolin—4(3H)—one Active 2—(4—(4—(2,5-dichiorothiophene-3—carbonyl)piperazin—1~yi)phenyl)—5,7— dimethoxyquinazolin—4(3H)-one Active 2-(4-(4-(cyciopropanecarbonyl)piperaziny|)pheny|)—5,7- dimethoxyquinazolin—4(3H)—one Active 2—(4—(4-(4-fluorobenzyl)piperazin—1—yi)phenyi)-5,7—dimethoxyquinazoiin— —i 4(3H)—one Active 2—(4—(4-benzylpiperazin—1—y|)pheny|)-5,7—dimethoxyquinazoiin-4(3H)—one Active 4—(2,2,2-trifluoroethyl)piperaziny|)pheny|)quinazolin-4(3H)-one Active—1 2-(4—(4—butyipiperaziny|)phenyl)—5,7-dimethoxyquinazolin—4(3H)—one Active ——] 2-(4-(4-acetyi—1,4-diazepan-1—yi)phenyl)—5,7-dimethoxyquinazolin—4(3H)- one Active 2—(4-(1,4-diazepanyl)pheny|)-5,7-dimethoxyquinazolin-4(3H)—one Active ,7—dimethoxy(4-(4-methyl-1,4—diazepanyi)pheny|)quinazolin-4(3H)- one Active N-(1-(4-(5,7-dimethoxyoxo-3,4—dihydroquinazoiin-2—yl)phenyi)piperidin y|)-N-ethyiacetamide Active 2-(4-((3R,58)—4-acetyI-3,5-dimethylpiperazin-1—y|)phenyi)—5,7— dimethoxyquinazolin—4(3H)—one Active 2-(4—((3R,5S)-3,5-dimethyipiperazinyl)phenyI)-5,7-dimethoxyquinazoiin— 4(3H)—one Active 2—(4—(4—acetyImethylpiperazin—1—y|)pheny|)—5,7-dimethoxyquinazolin- 4(3H)—one Active N-(1-(4-(5,7-dimethoxyoxo—3,4—dihydroquinazolinyl)phenyl)pyrrolidin- 3—yi)acetamide 2-(4-(4-isopropylpiperazinyi)phenyI)—8—methoxyquinazoiin-4(3H)—one Active 2—(4—(4—(2-hydroxyethyl)piperaziny|)pheny|)—5,7-dimethoxyquinazoiin- 4(3H)—one Active N-(1-(4-(5,7-dimethoxyoxo-3,4—dihydroquinazoiin—2—yl)phenyl)piperidin yi)-N—isopropylacetamide Active -chloro—2—(4—(4-isopropyipiperazin—1—yl)phenyi)quinazolin—4(3H)-one 2-(4-((3R,58)—4-isopropyi-3,5-dimethylpiperazin—1-y|)pheny|)—5,7— dimethoxyquinazolin—4(3H)—one ‘ 5,7—dimethoxy-Z—(4—(piperidinyi)phenyl)quinazolin-4(3H)-one ,7-dimethoxy—2—(4—(3-(methylamino)pyrroiidiny|)pheny|)quinazolin—4(3H)— one Active 2—(4-((4-isopropyipiperaziny|)methyl)phenyl)—5,7—dimethoxyquinazolin- 4(3H)—one 2-(4-(4—(isopropyiamino)piperidiny|)phenyi)—5,7—dimethoxyquinazolin— 4(3H)—one 2—(4-(1-acety|piperidin—4-yl)phenyI)—5,7-dimethoxyquinazolin-4(3H)-one ,7-dimethoxy-2—(4—(3—methylpiperaziny|)phenyl)quinazolin-4(3H)—one N-benzyI-N—(1—(5—(5,7—dimethoxyoxo-3,4-dihydroquinazolinyi)pyridin~2— yi)piperidin-4—yl)acetamide 2—(6-(4—(benzyiamino)piperidinyi)pyridin—3-yI)-5,7-dimethoxyquinazolin— 4(3H)-one 4-(4-(5,7—dimethoxyoxo—3,4—dihydroquinazolinyi)phenyl)piperazine-1 - carbaldehyde Active ,7—dimethoxy-Z-(4-(4-oxopiperidin—1—y|)phenyl)pyrido[2,3—d]pyrimidin- 4(3H)—one Active utyl 4-(4-(5,7—dimethoxyoxo—3,4—dihydroquinazolin-2— yi)phenyi)piperidine—1—carboxy|ate Active 2—(4-(dimethylamino)naphthaien—1-yi)—6,7—dimethoxyquinazolin—4(3H)-one Active 2-(4-(bis(2-hydroxyethyl)amino)phenyi)-5,7-dimethoxypyrido[2,3- d]pyrimidin—4(3H)-one Active 2—(2-(hydroxymethyI)—1H—indoIyi)-5,7-dimethoxyquinazolin-4(3H)—one Active 2—(2—(2—hydroxyethyi)—1H-indoI—5—yl)—5,7-dimethoxyquinazolin—4(3H)-one Active methoxy-Z—(2—(pyrroiidin-1—yimethyl)—1H—indoIy|)quinazoiin—4(3H)- one Active 2—(3-(hydroxymethyI)—1H-indazoIyI)—5,7—dimethoxyquinazoiin-4(3H)—one W" ,7-dimethoxy-Z-(Z—(2-(pyrrolidin—‘l-yl)ethyi)-1H—indoi-5—yl)quinazolin-4(3H)— one Active 2-(2-((dimethyiamino)methyi)—1H—indoI—5—yi)—5,7-dimethoxyquinazolin—4(3H)— one Active N—(4—(5,7-dimethoxyoxo-3,4—dihyd roquinazolin-Z— y|)phenyl)methanesuifonamide Active ,7—dimethoxy-2—(4-(pyridin-4—yiamino)pheny|)quinazoiin—4(3H)-one Active ,7-dimethoxy-Z-(4-(p—tolylamino)phenyl)quinazoiin-4(3H)—one W ,7—dimethoxy-Z-(4-(pyridin-3—ylamino)phenyi)quinazoiin—4(3H)—one Active —dimethyI(2—morpholinoethoxy)phenyi)-6,8-dimethoxyisoquinolin- 1(2H)—one Active 2-(3,5-dimethyi(2—morpholinoethoxy)phenyi)—5,7-dimethoxyquinazoiin- 4(3H)-one Active 3-(3,5—dimethyl(2—(4-methylpiperazin—1~y|)ethoxy)phenyI)—6,8— dimethoxyisoquinoiin-1(2H)-one Active 2-(3,5~dimethy|—4-(2-morpholinoethoxy)phenyl)quinazolin—4(3H)—one 7-(3,5—dimethyl—4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1 ,6- naphthyridin-5(6H)—one ,7—dimethoxy-2—(4-((4-methylpiperaziny|)methyl)phenyi)quinazolin- 4(3H)—one ,7-dimethoxy—2—(4—(morpholinomethyl)pheny|)quinazolin-4(3H)—one 2-(4-((4—ethyipiperaziny|)methyl)phenyI)—5,7—dimethoxyquinazoiin—4(3H)- 2—(3,5—dimethyl—4-(2—(pyrrolidinyi)ethoxy)phenyl)-5,7- dimethoxyquinazolin—4(3H)-one 4—(4—(5,7—dimethoxy-4—oxo—3,4-dihydroquinazolin-2—y|)phenoxy)-N,N— dimethylpiperidine—1—carboxamide 2-(4-(1-acety|piperidin—4—yloxy)phenyI)—5,7—dimethoxyquinazoiin—4(3H)—one 2—(isoindoiin—2—y|)ethoxy)—3,5-dimethylphenyi)—5,7- dimethoxyquinazolin-4(3H)-one 2-(3,5—dimethyl—4-(2-(pyrrolidin-1—yi)ethoxy)pheny|)methoxyquinazolin- 4(3H)—one ,7-dichioro—2—(3,5—dimethyi—4-(2—(pyrroiidin—1-y|)ethoxy)pheny|)quinazolin— 2-(3,5-dimethyl(3-(pyrrolidin-1—y|)propoxy)phenyI)-5,7—dimethoxy(3- (pyrrolidin-1—y|)propy|)quinazolin-4(3H)—one 2—(4—(2-(4—acetyipiperazin—1—y|)ethoxy)-3,5-dimethylphenyi)-5,7- dimethoxyquinazolin-4(3H)-one 2—(4—(2-(1H—imidazoly|)ethoxy)—3,5—dimethylphenyI)—5,7- dimethoxyquinazoiin—4(3H)-one —dimethyI-4—(2-(pyrroiidinyl)ethoxy)phenyI)—7—methoxyquinazolin— { 4(3H)-one Active ’ 2—(3,5-dimethyl(2—(4-methylpiperazin—1-y|)ethoxy)phenyi)—5,7-dimethoxyquinazolin—4(3H)—one Active 2—(3,5-dimethyI—4—(2-(piperidin-1—y|)ethoxy)phenyl)-5,7-dimethoxyquinazolin- 4(3H)—one Active ,7—dimethoxy—2—(3—methyl(2—(pyrrolidin—1—yi)ethoxy)phenyl)quinazoiin- 4(3H)-one Active 3—(2-(4-(5,7—dimethoxy—4—oxo-3,4-dihydroquinazoiin-Z-yl)-2,6— dimethyiphenoxy)ethyI)isopropy|imidezolidine-ZA—dione 2—(3,5-dimethyi—4—(3-(pyrroiidin-1—yl)propoxy)phenyi)—5,7— dimethoxyquinazoiin-4(3H)-one ,7-dimethoxy-2—(4-(2-(pyrrolidin—1-y|)ethoxy)phenyl)quinazolin—4(3H)—one 2-(3,5-dimethyl—4—(3-(pyrrolidiny|)propy|)phenyi)—5,7-dimethoxyquinazoiin— 4(3H)—one 2-(3,5—dimethyi—4-(4-(pyrrolidin-1—yl)butoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one Active 2-(3,5-dimethyI—4—(2—(pyrrolidinyi)ethoxy)pheny|)-8—methoxyquinazoiin- 4(3H)-one Active 3-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazoiin—Z-yI)-2,6- dimethylphenoxy)ethy|)—5-phenylimidazolidine-2,4—dione Active 3-(4-(5,7-dimethoxy—4—oxo—3,4-dihyd roquinazolin-Z—yl)benzyi)imidazoiidine— 2,4-dione Active 2-(3,5-dimethyI—4-(2—(pyrroiidin-1—yl)ethoxy)phenyI)—6—methoxyquinazolin— one Active 2-(3,5-dimethyI—4—(2—(pyrroiidiny|)ethoxy)phenyI)—5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one Active 2—(3,5—dimethyI(2-(pyrroiidin—1—y|)ethoxy)phenyi)-7—fiuoro—S—(pyrrolidin-1 - y|)quinazoiin-4(3H)—one Active -chioro—Z—(S,5-dimethyi(2—(pyrrolidinyi)ethoxy)phenyi)quinazoiin- 4(3H)—one Active 2-(4-(2-(azepan-1—y|)ethoxy)—3,5—dimethylphenyi)-5,7-dimethoxyquinazolin— 4(3H)—one Active -dimethyl—4—(2—(pyrroiidiny|)ethoxy)phenyl)-5,7—difluoroquinazolin—_l— 4(3H)-one Active 2—(4—(2—(azetidinyi)ethoxy)—3,5—dimethylphenyl)—5,7-dimethoxyquinazolin- 4(3H)—one Active 2-(4-(5,7-dimethoxyoxo—3,4-dihydroquinazolin—Z-yI)-2,6- dimethylphenoxy)ethy|)azetidin—3—yi)acetamide Active 2-(3,5—dimethyi(2—(pyrrolidin—1—yl)ethoxy)phenyI)-5,7- ropoxyquinazolin—4(3H)—one Active 8-chloro—2—(3,5-dimethyi—4—(2-(pyrrolidin—1-y|)ethoxy)phenyi)quinazoiin- 4(3H)—one Active 2—(3,5—dimethyi-4—(2—(pyrrolidin—1-yi)ethoxy)phenyI)—5,7-dimethquuinazolin- 4(3H)-one 2-(2-(4—(6,8—dimethoxyoxo-1,2—dihydroisoquinolin—3-yI)-2,6— dimethylphenoxy)ethyi)isoindo|ine—1,3-dione 2-(3,5—dimethyl-4—(2—(pyrrolidin-1—yi)ethoxy)phenyI)—5,7— diisopropoxypyrido[2,3—d1pyrimidin-4(3H)—one 2—(2-(4—(5,7—dimethoxyoxo—3,4—dihyd roquinazolin—Z—yi)—2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione (S)—2—(3,5-dimethyI—4—((5—oxopyrrolidin—2—yl)methoxy)phenyI)—5,7- dimethoxyquinazolin—4(3H)—one Active 2—(4—((4-isopropylpiperaziny|)methyi)pheny|)-5,7—dimethoxyquinazoiin- 4(3H)—one Active N-(1-(4—(5,7-dimethoxy—4—oxo—3,4-dihydroquinazolinyl)benzyl)piperidin y|)—N—isopropyiacetamide Active 2-(4—((4—(isopropyiamino)piperidiny|)methyl)phenyI)-5,7— dimethoxyquinazolin—4(3H)—one Active l 2-(4-((1H—tetrazoI-S-yl)methyl)phenyl)—5,7-dimethoxyquinazolin—4(3H)—one Active 1-(2—(4—(5,7—dimethoxyoxo—3,4-dihydroquinazoiin-Z-yi)—2,6— dimethylphenoxy)ethyi)pyrroiidine-2,5—dione Active 7-(2-(benzyloxy)ethoxy)—5—methoxy-2—(pyridinyl)quinazolin—4(3H)—one Active —dimethylpyridin—4-yI)—5,7—dimethoxyquinazoiin-4(3H)—one 2-(2,6-dimethylpyridin-4—y|)-5—methoxy(2—methoxyethoxy)quinazolin— 4(3H)—one Active 2—(2,6—dimethy|pyridin—4-y|)-5,7-bis(2—methoxyethoxy)quinazolin-4(3H)-one Active ’ 2-(2,6—dimethylpyridin—4—yI)—7—methoxy—5-(2—(pyrroIidin-1 - y|)ethoxy)quinazoiin—4(3H)—one Active ' } 4(3H)—one ~1— 2—(2,6—dimethylpyridiny|)—6-((4—methy|piperazin-1—y|)methy|)quinazolin- Active l 2-(2,6-dimethyipyridin-4—yl)-5—methoxy-7—(2—phenoxyethoxy)quinazolin- 4(3H)—one Active 2-(2,6-dimethylpyridiny|)-7—methoxy—5-(2—phenoxyethoxy)quinazolin- 4(3H)-one Active 2-(2,6-dimethylpyridin-4—y|)—7—methoxy(2-methoxyethoxy)quinazolin- 4(3H)—one Active I 2-(2,6—dimethylpyridin—4—yl)methoxy-7—(2—(pyrrolidin—1 — oxy)quinazolin-4(3H)—one Active —dimethylpyridin—4-y|)(2—isopropoxyethoxy)—5—methoxyquinazolin— 4(3H)-one Active 2-(2,6-dimethylpyridinyI)—5,7—bis(2-isopropoxyethoxy)quinazolin-4(3H)- one; ( Active 7—(2—(benzyloxy)ethoxy)(2,6—dimethylpyridin—4—yl)—5—methoxyquinazo|in- 4(3H)-one Active ’ 2-(2,6—dimethylpyridin-4—yl)—6—(2—morphoiinoethyi)quinazolin—4(3H)-one Active 2-(2—methylpyridinyi)—6-(morpholinomethyl)quinazolin—4(3H)-0ne Active -methoxy(2-methoxyethoxy)(2—methyipyridin-4—yl)quinazoiin-4(3H)— one Active 2—(2,6—dimethyipyridin—4—y|)(2—(pyrrolidinyl)ethyl)quinazolin-4(3H)—one Active 2—(2,6—dimethylpyridinyl)-7—(2—methoxyethoxy)—5—(2—(pyrrolidin-1 - yl)ethoxy)quinazolin-4(3H)-one 2—(3,5-dimethoxyphenyl)—5,7—dimethoxyquinazolin—4(3H)-one 2-(3-(2-hydroxyethoxy)phenyl)—5,7-dimethoxyq uinazolin-4(3H)-one Active 2—(3-(2-hydroxyethoxy)methylphenyl)—5,7-dimethoxyquinazolin-4(3H)—one Active ,7-dimethoxy—2-(3—methoxy—5-(2v(pyrrolidin-1—yl)ethoxy)phenyl)quinazolin- 4(3H)—one Active N-(2—(3—(5,7-dimethoxyoxo—3,4-dihydroquinazolin—Z—yl)—5— methoxyphenoxy)ethy|)acetamide Active 2-(3,5—dimethoxyphenyl)—6-(pyridin—4-ylamino)quinazo|in—4(3H)—one Active ,7-dimethoxy—2—(3—methoxyphenyl)quinazolin—4(3H)—one Active Example 128. fication of hVCAM mRNA In this example, hlL—6 mRNA in tissue culture cells was quantitated to measure the transcriptional inhibition of hVCAM when treated with a compound of the invention.

Human umbilical vein endothelial cells (HUVECs) were plated in a 96-well plate (4.O><103 cells/well) in 100 uL EGM media and incubated for 24 h prior to the on of the compound of interest. The cells were pretreated for 1 h with the test compound prior to stimulation with tumor necrosis -a. The cells were incubated for an additional 24 h before the cells were harvested. At time of harvest, the spent media was removed from the HUVECs and rinsed in 200 uL PBS. Cell lysis solution (70 pL) was then added the cells in each well and incubated for ~5—10 min at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the "mRNA Catcher PLUS plate" (lnvitrogen), according to the protocol ed. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. n buffer (E3, 70 uL) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer for 5 min at 68°C and then immediately placing the plate on ice.

The eluted mRNA so isolated was then used in a one—step quantitative real-time PCR reaction, using components of the Ultra Sense Kit together with Applied Biosystems -probe mixes. Real-time PCR data was analyzed, normalizing the Ct values for hVCAM to an internal control, prior to determining the fold ion of each n sample, relative to the control.

In Table 3, an active nd is one that causes a 2 20% inhibition in VCAM-1 mRNA at a concentration less than or equal to 10 pM.

Table 3.

Inhibition of VCAM—1 Example expression 2-(4—(4-isopropylpiperazinyl)phenyI)-5,7-dimethoxyquinazolin-4(3H)— one Active 2-(4—(4-acetylpiperazin—1-y|)phenyI)-5,7-dimethoxyquinazolin-4(3H)—one Active ,7—dimethoxy(4-(piperazin—1~yl)phenyl)quinazolin—4(3H)-one Active N-(1-(4-(5,7-dimethoxyoxo—3,4—dihydroquinazolin—2—yl)phenyl)piperidin- 4-yl)acetamide Active 2—(4-(4-hexanoylpiperazin-l-y|)phenyI)—5,7—dimethoxyquinazolin-4(3H)- one Inactive 2-(4—(4—isobutyrylpiperazin—1-yl)phenyl)-5,7-dimethoxyquinazolin—4(3H)- one Active 2-(4—(4—benzoylpiperazin-1—yl)phenyl)—5,7-dimethoxyquinazolin-4(3H)—one Active 2—(4-(4-(4-fluorobenzoyl)piperazinyl)phenyl)-5,7-dimethoxyquinazolin- one Active N-(1-(4—(5,7—dimethoxyoxo—3,4—dihydroquinazolin—2—yl)phenyl)piperidin— 4-yl)benzamide Active 2-(4-(4-(5-chloro—1—methyl-1H-pyrazole—4-carbonyl)piperazin—1-yl)phenyl)- ,7-dimethoxyquinazolin-4(3H)—one Active ,7-dimethoxy—2—(4—(4-(3,3, luoropropanoyl)piperazin—1 - yl)phenyl)quinazolin-4(3H)-one Active 2-(4—(4—(2,5-dichlorothiophene—3-carbonyl)piperazinyl)phenyl)—5,7- dimethoxyquinazolin—4(3H)-one Active 2-(4—(4—(cyclopropanecarbonyl)piperazin—1-yl)phenyl)-5,7— dimethoxyquinazolin-4(3H)-one Active 2—(4-(4—(2,2,2-trifluoroethyl)piperazin—1—yl)phenyl)quinazolin-4(3H)-one Inactive 2—(4-(4-butylpiperazinyl)phenyI)—5,7-dimethoxyquinazolin—4(3H)—one Active 2-(4-(1,4-diazepan-1—yl)phenyl)-5,7-dimethoxyquinazolin—4(3H)-one ‘ Active ,7—dimethoxy—Z-(4—(4—methyl-1,4-diazepan—1-yl)phenyl)quinazolin—4(3H)- one Active N-(1-(4-(5,7—dimethoxy—4-oxo—3,4-dihydroquinazolin—2—yl)phenyl)piperidin- 4-yl)—N-ethylacetamide Active 2—(4-((3R,58)—4-acetyI—3,5—dimethylpiperazin—1—yl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one Active 2-(4-((3R,58)—3,5—dimethyipiperaziny|)phenyI)—5,7- dimethoxyquinazolin-4(3H)-one 2—(4—(4—acetyImethylpiperaziny|)phenyl)—5,7-dimethoxyquinazolin- N-(1-(4-(5,7-dimethoxy—4—oxo—3,4-dihydroquinazolin—Z— yI)phenyl)pyrrolidin—3-yl)acetamide 2-(4-(4—isopropylpiperazinyl)phenyI)methoxyquinazolin-4(3H)-one 2-(4-(4-(2—hydroxyethyl)piperazinyl)phenyI)—5,7—dimethoxyquinazolin— 4(3H)-one 2-(4-(dimethylamino)naphthalenyI)-6,7-dimethoxyquinazolin-4(3H)—one Active ,7—dimethoxy-2—(2-(pyrr0lidin—1—y|methyI)-1 I—5-yl)quinazolin—4(3H)- one Active ,7-dimethoxy-Z—(Z—(2—(pyrrolidiny|)ethy|)-1H-indoI—5—yl)quinazolin- 4(3H)—one Active 2-(2—((dimethylamino)methyi)—1H—indoI—5—yI)—5,7-dimethoxyquinazolin— 4(3H)—one ,7—dimethoxy-2—(4-(pyridin—3—ylamino)phenyl)quinazolin-4(3H)-one 2-(3,5-dimethyl—4—(2—morpholinoethoxy)phenyI)-5,7-dimethoxyquinazolin- 4(3H)-one 2-(3,5—dimethyI—4-(2-morphoiinoethoxy)phenyl)quinazolin-4(3H)—one 7-(3,5-dimethyl-4—(2—morpholinoethoxy)phenyl)—2,4—dimethoxy—1 ,6- naphthyridin—5(6H)—one 2-(4-((4-ethylpiperazinyl)methyl)phenyl)—5,7—dimethoxyquinazolin- 4(3H)—one 2-(3,5-dimethyl—4—(2—(pyrrolidiny|)ethoxy)phenyI)—5,7- dimethoxyquinazolin—4(3H)—one 2—(4-(2-(isoindolinyl)ethoxy)—3,5—dimethylphenyI)-5,7- dimethoxyquinazolin—4(3H)-one 2—(3,5—dimethyl(2—(pyrrolidin-1—yl)ethoxy)pheny|)methoxyquinazolin— 4(3H)-one Active ,7-dichloro-2—(3,5-dimethyl(2—(pyrroIidin—1- yl)ethoxy)phenyl)quinazolin-4(3H)-one 2-(4-(2-(4-acetylpiperazin—1~yl)ethoxy)-3,5—dimethylphenyl)—5,7— dimethoxyquinazolin—4(3H)—one 2-(1H-imidazoIyl)ethoxy)-3,5-dimethylphenyl)—5,7- dimethoxyquinazolin-4(3H)-one 2-(3,5-dimethyI—4—(2-(pyrrolidin-1—yl)ethoxy)phenyI)—7-methoxyquinazolin— 4(3H)—one 2-(3,5-dimethyI(2-(4—methylpiperazin-1—y|)ethoxy)phenyi)-5,7- dimethoxyquinazoiin-4(3H)—one Active 2—(3,5-dimethyI(2-(piperidinyi)ethoxy)phenyI)—5,7— dimethoxyquinazolin-4(3H)-one Active ,7—dimethoxy(3—methy|—4—(2—(pyrrolidinyi)ethoxy)phenyl)quinazo|in- 3-(2—(4-(5,7-dimethoxy4-oxo—3,4-dihydroquinazolin-Z—yI)-2,6- ylphenoxy)ethyI)isopropyiimidazoiidine—2,4-dione Active 2-(3,5—dimethyl(3-(pyrroiidin—1—y|)propy|)phenyi)—5,7— dimethoxyquinazolin—4(3H)—one Active 2-(3,5—dimethyi—4-(4-(pyrroiidiny|)butoxy)phenyi)—5,7- dimethoxyquinazolin-4(3H)—one Active 2-(3,5—dimethyl(2—(pyrroiidin—1—y|)ethoxy)phenyI)methoxyquinazolin- 4(3H)—one Active 3-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolin—2-yI)-2,6— dimethyiphenoxy)ethyI)-5—phenyiimidazoiidine—Z,4-dione Active 3-(4-(5,7-dimethoxyoxo—3,4-dihyd roquinazolin—Z— y|)benzy|)imidazolidine-2,4—dione Active 2-(3,5-dimethyl—4-(2-(pyrrolidin—1—y|)ethoxy)pheny|)methoxyquinazolin— 4(3H)-one Active 2-(3,5-dimethyl(2-(pyrro|idin—1—y|)ethoxy)phenyI)—5,7- dimethoxypyrido[2,3-d]pyrimidin~4(3H)-one Active 2-(3,5-dimethyl—4—(2—(pyrroiidin-1—y|)ethoxy)phenyl)f|uoro—5-(pyrro|idin- uinazo|in-4(3H)—one Active -chloro-2—(3,5-dimethyi-4—(2-(pyrrolidiny|)ethoxy)pheny|)quinazolin- 4(3H)-one ActiveL 2—(4—(2-(azepan—1-y|)ethoxy)-3,5-dimethylphenyi)—5,7- dimethoxyquinazoiin—4(3H)-one Active 2-(3,5-dimethyl(2—(pyrrolidiny|)ethoxy)phenyi)—5,7-difluoroquinazolin- one Active 2-(2—(4—(5,7-dimethoxy—4—oxo—3,4-dihydroquinazolin-Z—yI)-2,6- dimethyiphenoxy)ethyi)isoindoline—1,3—dione Active (S)—2-(3,5-dimethyl—4—((5—oxopyrrolidin-Z-yi)methoxy)pheny|)—5,7- dimethoxyquinazolin-4(3H)-one Active 1—(2—(4—(5,7-dimethoxy—4—oxo-3,4-dihydroquinazoiin-Z-yI)-2,6- dimethyiphenoxy)ethyi)pyrroiidine-Z,5-dione Active I 7-(2—(benzyloxy)ethoxy)methoxy—2-(pyridinyl)quinazolin—4(3H)—one Active 2-(2,6-dimethylpyridiny|)—5,7-bis(2-methoxyethoxy)quinazolin—4(3H)- one Active 2—(2,6—dimethyipyridinyl)methoxy-5—(2—(pyrro|idin-1 - y|)ethoxy)quinazolin-4(3H)-0ne 2-(2,6-dimethylpyridiny|)methoxy—7-(2—phenoxyethoxy)quinazoiin- 4(3H)—one Active 2-(2,6-dimethylpyridin—4-yi)tnethoxy(2-phenoxyethoxy)quinazolin- 4(3H)-one Active 2—(2,6-dimethyipyridinyl)—7-methoxy—5-(2—methoxyethoxy)quinazolin- 4(3H)—one Inactive 2—(2,6—dimethyipyridin-4—y|)methoxy(2-(pyrrolidin-1 - yi)ethoxy)quinazolin-4(3H)—one inactive l 2—(2,6—dimethyipyridinyI)(2-isopropoxyethoxy)—5—methoxyquinazolin—4(3H)—one l 2—(2,6-dimethy|pyridin—4—yI)-5,7-bis(2-isopropoxyethoxy)quinazoiin—4(3H)-one; 7-(2-(benzyioxy)ethoxy)—2—(2,6—dimethylpyridinyi)methoxyquinazolin- 4(3H)—one Active 2-(2,6—dimethy|pyridinyi)—6—(2-morpho|inoethyl)quinazolin-4(3H)—one l Inactive 2—(2—methylpyridinyl)-6—(morphoiinomethy|)quinazolin—4(3H)—one i inactive -methoxy(2—methoxyethoxy)~2-(2—methylpyridiny|)quinazolin-4(3H)— one Active 2-(2,6-dimethyipyridin—4—yl)—6-(2-(pyrrolidinyl)ethyl)quinazolin-4(3H)— one Active 2-(2,6—dimethyipyridiny|)—7-(2—methoxyethoxy)(2—(pyrrolidin—1 - yl)ethoxy)quinazoiin—4(3H)-one Active 2-(3,5-dimethoxyphenyI)—5,7—dimethoxyquinazolin-4(3H)—one Active 2-(3-(2—hydroxyethoxy)phenyI)-5,7—dimethoxyquinazolin-4(3H)-one Active 2—(3-(2—hyd roxyethoxy)methy|pheny|)—5,7—dimethoxyquinazolin-4(3H)— ,7—dimethoxy(3-methoxy(2—(pyrrolidin—1 — y|)ethoxy)phenyl)quinazo|in-4(3H)-one Active 3-(5,7—dimethoxy-4—oxo-3,4-dihydroquinazolin—Z—yI)—5- yphenoxy)ethy|)acetamide Active -dimethoxyphenyl)—6—(pyridin—4—ylamino)quinazolin—4(3H)-one Inactive ,7-dimethoxy(3-methoxyphenyl)quinazoiin-4(3H)—one Active Other embodiments of the invention as described herein are defined in the ing aphs: 1. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a therapeutically effective amount of at least one compound of or a isomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q and V are independently selected from CH and nitrogen; U is selected from C=O, C=S, SO2, S=O, SR1, CR1R2, CR1OR2, CR1SR2; R1 and R2 are independently selected from hydrogen and C1-C6 alkyl; Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C3-C6 cycloalkyl, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be ted to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkenyl, C3-C6 cycloalkyl, hydroxyl, and amino; Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 , C3-C6 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle; represents a 3-8 membered ring system wherein: W is selected from carbon and nitrogen; Z is selected from CR6R7, NR8, oxygen, sulfur, -S(O)-, and -SO2-; said ring system being optionally fused to another ring selected from lkyl, heterocycle, and phenyl, and wherein said ring system is optionally selected from rings having the structures R3, R4, and R5 are ndently selected from hydrogen, C1-C6 alkyl, C1- C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryl, aryloxy, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, aryl, halogen, hydroxyl, -CN, amino, and amido; and R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, acyl, and C3-C6 cycloalkyl; and R9, R10, R11, and R12 are independently selected from en, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 lkyl, aryl, cycle, hydroxyl, sulfonyl, and acyl, provided that if Q = CH, then at least one of Ra1, Ra2, and Ra3 is not hydrogen; if Z = NAc, then only one of Ra1, Ra2, or Ra3 is hydrogen, and Ra1 is not -OCH2CH2OMe; and if Ra1 and Ra3 are both OMe, then R8 is not -C(O)CH2OH. 2. The method according to paragraph 1, wherein is R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, acyl, and C1-C6 3. The method ing to paragraph 1, wherein is N R10 R3 and R4 are independently ed from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R9 and R10 are independently ed from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, aryl, heterocycle, sulfonyl, carbamate, carboxamide, and acyl. 4. The method according to paragraph 1, wherein is R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 l, C1-C6 l, C1-C6 alkoxy, C3-C6 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amido, oxo, -CN, and sulfonamide; and R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, acyl, and C3-C6 cycloalkyl.

. The method according to paragraph 1, wherein U is C=O Rc is hydrogen; Ra2 is hydrogen; Ra1 and Ra3 are independently selected from C1-C6 alkoxy, hydrogen, and halogen; Rb2, Rb3, Rb5, and Rb6 are each hydrogen; R4 R4 is selected from , , , and ; R3 and R4 are independently selected from hydrogen and C1-C6 alkyl; R8 is ed from C1-C6 alkyl and hydrogen; and R9, R10, R11, and R12 are independently selected from C1-C6 alkyl, hydrogen, acyl, and sulfonyl. 6. The method according to paragraph 5, wherein U is C=O Rc is hydrogen; Ra2 is hydrogen; Ra1 and Ra3 are independently ed from methoxy, hydrogen, and halogen; Rb2, Rb3, Rb5, and Rb6 are each hydrogen; R3 R3 N R10 R4 R4 is selected from , , , and ; R3 and R4 are independently selected from en and methyl; R8 is selected from hydrogen, hydroxyethyl, butyl, acetyl, isopropyl, 4- hexanoyl, 4-isobutyryl, benzoyl, 4-fluorobenzoyl, 4-picolinoyl, 4-nicotinoyl, 4- isonicotinoyl, thiophenecarbonyl, 5-chloromethyl-1H-pyrazolecarbonyl, trifluoropropanoyl, 2,5-dichlorothiopenecarbonyl, ropanecarbonyl, 4-fluorobenzyl, benzyl, trifluoroethyl, tertbutoxycarbonyl, and formyl; R9 and R10 are independently selected from hydrogen, methyl, cyclopropylmethyl, and acetyl; and R11 and R12 are independently selected from hydrogen, acetyl, methanesulfonyl, dimethylaminocarbonyl, benzoyl, , ethyl, and isopropyl. 7. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a therapeutically effective amount of at least one compound selected from: ,7-dimethoxy(4-morpholinophenyl)quinazolin-4(3H)-one; 2-(4-((3R,5S)acetyl-3,5-dimethylpiperazinyl)phenyl)-5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2-(4-(4-hydroxypiperidinyl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin- 4(3H)-one; 2-(4-((3R,5S)acetyl-3,5-dimethylpiperazinyl)phenyl)methoxy(2- methoxyethoxy)quinazolin-4(3H)-one; 2-(4-(4-isopropylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-acetylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(piperazinyl)phenyl)quinazolin-4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin tamide; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)methanesulfonamide; 3-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)-1,1-dimethylurea; 2-(4-(4-hexanoylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-isobutyrylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-benzoylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-(4-fluorobenzoyl)piperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)benzamide; ,7-dimethoxy(4-(4-picolinoylpiperazinyl)phenyl)quinazolin-4(3H)-one; ,7-dimethoxy(4-(4-nicotinoylpiperazinyl)phenyl)quinazolin-4(3H)-one; 2-(4-(4-isonicotinoylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)- ,7-dimethoxy(4-(4-(thiophenecarbonyl)piperazin nyl)quinazolin-4(3H)-one; 2-(4-(4-(5-chloromethyl-1H-pyrazolecarbonyl)piperazinyl)phenyl)- ,7-dimethoxyquinazolin-4(3H)-one; methoxy(4-(4-(3,3,3-trifluoropropanoyl)piperazin yl)phenyl)quinazolin-4(3H)-one; 2-(4-(4-(2,5-dichlorothiophenecarbonyl)piperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(4-(cyclopropanecarbonyl)piperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(4-(4-fluorobenzyl)piperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(4-benzylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-(2,2,2-trifluoroethyl)piperazinyl)phenyl)quinazolin-4(3H)-one; 2-(4-(4-butylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-acetyl-1,4-diazepanyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)- 2-(4-(1,4-diazepanyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(4-methyl-1,4-diazepanyl)phenyl)quinazolin-4(3H)- N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)-N-ethylacetamide; 2-(4-((3R,5S)acetyl-3,5-dimethylpiperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-((3R,5S)-3,5-dimethylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(4-acetylmethylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)pyrrolidin- 3-yl)acetamide; 2-(4-(4-isopropylpiperazinyl)phenyl)methoxyquinazolin-4(3H)-one; 2-(4-(4-(2-hydroxyethyl)piperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)-N-isopropylacetamide; ro(4-(4-isopropylpiperazinyl)phenyl)quinazolin-4(3H)-one; (3R,5S)isopropyl-3,5-dimethylpiperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(piperidinyl)phenyl)quinazolin-4(3H)-one; ,7-dimethoxy(4-(3-(methylamino)pyrrolidinyl)phenyl)quinazolin- 4(3H)-one; tert-butyl 4-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidine- 1-carboxylate; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)pyrrolidin- 3-yl)-N-methylacetamide; 2-(4-(4-(isopropylamino)piperidinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(1-acetylpiperidinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(3-methylpiperazinyl)phenyl)quinazolin-4(3H)-one; N-benzyl-N-(1-(5-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)pyridin- 2-yl)piperidinyl)acetamide; 2-(6-(4-(benzylamino)piperidinyl)pyridinyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 4-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperazine carbaldehyde; 2-(4-(2-(1-acetylazetidinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(3-(cyclopropylmethylamino)pyrrolidinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; and ,7-dimethoxy(4-(4-oxopiperidinyl)phenyl)pyrido[2,3-d]pyrimidin- one, or a pharmaceutically acceptable salt or hydrate thereof. 8. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a therapeutically effective amount of at least one nd of Formula II: or a stereoisomer, er, pharmaceutically acceptable salt, or e thereof, wherein: Q and V are independently selected from CH and nitrogen; U is selected from C=O, C=S, SO2, S=O, SR1, CR1R2, CR1OR2, and CR1SR2; R1 and R2 are independently selected from hydrogen and C1-C6 alkyl; Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; Ra1, Ra2, and Ra3 are independently ed from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, amino, amide, hydroxyl, cycloalkyl, and heterocycle, n Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkenyl, C3-C6 cycloalkyl, hydroxyl, and amino; Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle; Rn1 is selected from hydrogen, C1-C6 alkyl, and C3-C6 lkyl; and Rn2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, alkenyl, sulfonyl and acyl, wherein Rn1 and/or Rn2 may be connected with Rb3 and or Rb5 to form a 5- or 6-membered cyclic ring, provided that at least one of Ra1, Ra2, and Ra3 are not hydrogen; and Rn1 and Rn2 are not both methyl or ethyl. 9. The method according to paragraph 8, wherein Q is CH and V is nitrogen; U is C=O; Rc is hydrogen; Ra2 is hydrogen; Ra1 and Ra3 are each C1-C6 alkyl; Rb2, Rb3, and Rb6 are each en; Rn1 is hydrogen; Rn2 is selected from sulfonyl, heterocycle, and aryl; and Rb5 is selected from hydrogen or may be ted with Rn2 to form a heterocycle.

. The method according to paragraph 9, wherein Q is CH and V; U is C=O; Rc is hydrogen; Ra2 is hydrogen; Ra1 and Ra3 are each methoxy; Rb2, Rb3, and Rb6 are each hydrogen; Rn1 is hydrogen; Rn2 is selected from methanesulfonyl, pyridinyl, 4-methylphenyl, and pyridinyl; and Rb5 is selected from hydrogen or may be connected with Rn2 to form a heterocycle selected from (2-hydroxymethyl)-1H-pyrrolyl, (2-hydroxyethyl)-1H- pyrrolyl, rolidinyl-ylmethyl)-1H-pyrrolyl, 3-(hydroxymethyl)-1H- lyl, 2-(pyrrolidinyl-ylethyl)-1H-pyrrolyl, and 2- ((dimethylamino)methyl)-1H-pyrrolyl. 11. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a eutically effective amount of at least one compound selected from: 2-(4-(dimethylamino)naphthalenyl)-6,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3- d]pyrimidin-4(3H)-one; 2-(2-(hydroxymethyl)-1H-indolyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-(2-hydroxyethyl)-1H-indolyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(2-(pyrrolidinylmethyl)-1H-indolyl)quinazolin-4(3H)- 2-(3-(hydroxymethyl)-1H-indazolyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(2-(2-(pyrrolidinyl)ethyl)-1H-indolyl)quinazolin-4(3H)- 2-(2-((dimethylamino)methyl)-1H-indolyl)-5,7-dimethoxyquinazolin- N-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolin yl)phenyl)methanesulfonamide; ,7-dimethoxy(4-(pyridinylamino)phenyl)quinazolin-4(3H)-one; ,7-dimethoxy(4-(p-tolylamino)phenyl)quinazolin-4(3H)-one; and ,7-dimethoxy(4-(pyridinylamino)phenyl)quinazolin-4(3H)-one, or a pharmaceutically acceptable salt or hydrate thereof. 12. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising stering a therapeutically ive amount of at least one compound of Formula III: (III) or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q is selected from CR12 and nitrogen; V is selected from CH and nitrogen; U is selected from C=O, C=S, SO2, S=O, SR1, CR1R2, CR1OR2, CR1SR2; X is selected from oxygen, sulfur, SR1, nitrogen, NR6R7, and CR6R7; Z is selected from unsubstituted C1-C6 alkyl and C1-C6 alkyl substituted with one or more groups ed from C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, hydroxyl, amino, and halogen; n is selected from 0, 1, 2, 3, 4, or 5; G is selected from heterocycle, cycloalkyl, and aryl; R1 and R2 are independently selected from hydrogen, and C1-C6 alkyl; R6, R7, and R12 are independently selected from hydrogen, C1-C6 alkyl, C3- C6 cycloalkyl, heterocycle, C1-C6 , and halogen; Rc is ed from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 lkyl, halogen, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently ed from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, hydroxyl, and amino; and Rb3 and Rb5 are independently ed from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle; provided that if Ra1 and Ra3 are OMe, and Q = CH, then is not H O O N N O N O N N Ph NAc O , O , or ; at least one of Ra1, Ra2, and Ra3 is not hydrogen; and if Ra2 or Ra3 is chloro, then Ra1 is not hydrogen. 13. The method according to paragraph 12, n U is C=O; Q is selected from CR12 and nitrogen; V is selected from nitrogen; Z is selected from unsubstituted C1-C6 alkyl; R12 is selected from C1-C6 alkoxy and halogen; Rc is ed from hydrogen and C1-C6 alkyl; Ra2 is selected from hydrogen and C1-C6 alkoxy; Ra1 and Ra3 are ndently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, and heterocycle; Rb2 and Rb6 are both hydrogen; Rb3 and Rb5 are independently selected from hydrogen and C1-C6 alkyl; X is selected from oxygen and CH2; n is selected from 0, 1, 2, 3, or 4; and G is selected from heterocycle, cycloalkyl, and aryl. 14. The method according to paragraph 13, wherein U is C=O; Q is selected from CR12 and nitrogen; V is selected from nitrogen; R12 is ed from methoxy and chlorine; Rc is selected from hydrogen and (pyrrolidinyl)propyl; Ra2 is selected from hydrogen and methoxy; Ra1 and Ra3 are independently selected from hydrogen, methyl, chlorine, fluorine, methoxy, isopropoxy, and pyrrolidinyl; Rb2 and Rb6 are both hydrogen; Rb3 and Rb5 are independently selected from hydrogen and methyl; and is selected from imethylpiperidinecarboxamide)oxy, 1- acetylpiperidinyloxy, 2-(isoindolinyl)ethoxy, rolidinyl)ethoxy, 3- (pyrrolidinyl)propoxy, 4-(pyrrolidinyl)butoxy, (4-acetylpiperazinyl)ethoxy, idazolyl)ethoxy, (4-methylpiperazinyl)ethoxy, (piperidinyl)ethoxy, (1-isopropylimidazolidine-2,4-dione)ethoxy, (5-phenylimidazolidine-2,4-dione)- 3-ethoxy, (imidazolidine-2,4-dione)methyl, (2-azepanyl)ethoxy, (2-azetidin oxy, N-(azetidinyl)acetamideethoxy, (isoindoline-1,3-dione)ethoxy, (5-oxopyrrolidinyl)methoxy, (4-isopropylpiperazinyl)methyl, N-isopropyl-N- (piperidinmethyl)acetamidemethyl, (4-(isopropylamino)piperidinyl)methyl, (pyrrolidine-2,5-dione)ethoxy, and (1H-tetrazolyl)methyl.

. A method for reducing IL-6 and/or VCAM-1 in a t, comprising administering a therapeutically effective amount of at least one compound selected from: 3-(3,5-dimethyl(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin- 1(2H)-one; 2-(3,5-dimethyl(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 3-(3,5-dimethyl(2-(4-methylpiperazinyl)ethoxy)phenyl)-6,8- dimethoxyisoquinolin-1(2H)-one; 2-(3,5-dimethyl(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one; 7-(3,5-dimethyl(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6- naphthyridin-5(6H)-one; ,7-dimethoxy(4-((4-methylpiperazinyl)methyl)phenyl)quinazolin- ,7-dimethoxy(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one; 2-(4-((4-ethylpiperazinyl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)- 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 4-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenoxy)-N,N- dimethylpiperidinecarboxamide; 2-(4-(1-acetylpiperidinyloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(isoindolinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 4(3H)-one; ,7-dichloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 2-(3,5-dimethyl(3-(pyrrolidinyl)propoxy)phenyl)-5,7-dimethoxy(3- (pyrrolidinyl)propyl)quinazolin-4(3H)-one; 2-(4-(2-(4-acetylpiperazinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(2-(1H-imidazolyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(4-methylpiperazinyl)ethoxy)phenyl)-5,7- oxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(piperidinyl)ethoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(3-methyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 3-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)isopropylimidazolidine-2,4-dione; 2-(3,5-dimethyl(3-(pyrrolidinyl)propoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)-one; 2-(3,5-dimethyl(3-(pyrrolidinyl)propyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(4-(pyrrolidinyl)butoxy)phenyl)-5,7- oxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 4(3H)-one; 3-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)phenylimidazolidine-2,4-dione; 3-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)benzyl)imidazolidine- 2,4-dione; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)fluoro(pyrrolidin yl)quinazolin-4(3H)-one; ro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 2-(4-(2-(azepanyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-difluoroquinazolin- 4(3H)-one; 2-(4-(2-(azetidinyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)azetidinyl)acetamide; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- diisopropoxyquinazolin-4(3H)-one; 8-chloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-dimethylquinazolin- 4(3H)-one; 4-(6,8-dimethoxyoxo-1,2-dihydroisoquinolinyl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- ropoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione; (S)(3,5-dimethyl((5-oxopyrrolidinyl)methoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-((4-isopropylpiperazinyl)methyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)benzyl)piperidin yl)-N-isopropylacetamide; 2-(4-((4-(isopropylamino)piperidinyl)methyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; and 2-(4-((1H-tetrazolyl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one, or a pharmaceutically acceptables salt or hydrate thereof. 16. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a therapeutically effective amount of at least one nd of Formula IV: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q1 is ed from nitrogen and C-Ra1; Q2 is selected from nitrogen and C-Ra2; Q3 is selected from nitrogen and C-Ra3; V is ed from CH and nitrogen; U is selected from C=O, C=S, SO2, S=O, SR1, CR1R2, CR1OR2, ; R1 and R2 are independently selected from hydrogen and C1-C6 alkyl; Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and heterocycle, n Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, hydroxyl, and amino; and Rb3 and Rb5 are ndently selected from hydrogen, methyl, ethyl, C3- C6 cycloalkyl, C1-C3 alkoxy, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, ed that if Ra3 is , then Ra1 is not hydrogen; N N if Ra2 is or O , then Rb 3 is not hydrogen; and if Rb2, Rb5, and Rb6 are hydrogen, then Rb3 is not -CH2OH. 17. The method according to paragraph 16, wherein U is C=O V is nitrogen; Rb2 and Rb6 are both hydrogen; Rb3 and Rb5 are independently selected from C1-C6 alkyl and hydrogen; Q2 is selected from C1-C6 alkyl and hydrogen; and Q1 and Q3 are independently selected from hydrogen and C1-C6 alkoxy. 18. The method according to paragraph 17, wherein U is C=O; V is nitrogen; Rb2 and Rb6 are both hydrogen; Rb3 and Rb5 are independently selected from methyl and hydrogen; Q2 is selected from hydrogen, (4-methylpiperazinyl)methyl, morpholinoethyl, morpholinomethyl, and (pyrrolidinyl)ethyl; and Q1 and Q3 are ndently selected from hydrogen, benzyloxyethoxy, methoxy, methoxyethoxy, (pyrrolidinyl)ethoxy, phenoxyethoxy, and isopropoxyethoxy. 19. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a therapeutically ive amount of at least one compound ed from: 4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)pyrrolidine-2,5-dione; 7-(2-(benzyloxy)ethoxy)methoxy(pyridinyl)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-methoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-(pyrrolidin yl)ethoxy)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)((4-methylpiperazinyl)methyl)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-phenoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-phenoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-methoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-(pyrrolidin oxy)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)(2-isopropoxyethoxy)methoxyquinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)-5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)- 7-(2-(benzyloxy)ethoxy)(2,6-dimethylpyridinyl)methoxyquinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)(2-morpholinoethyl)quinazolin-4(3H)-one; 2-(2-methylpyridinyl)(morpholinomethyl)quinazolin-4(3H)-one; -methoxy(2-methoxyethoxy)(2-methylpyridinyl)quinazolin-4(3H)- 2-(2,6-dimethylpyridinyl)(2-(pyrrolidinyl)ethyl)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)(2-isopropoxyethoxy)methoxyquinazolin- 4(3H)-one; and 2-(2,6-dimethylpyridinyl)(2-methoxyethoxy)(2-(pyrrolidin yl)ethoxy)quinazolin-4(3H)-one, or a pharmaceutically acceptable salt or hydrate f.

. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a eutically effective amount of at least one compound of Formula V: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q is selected from CR6 and nitrogen; U is selected from C=O, C=S, SO2, S=O, SR1, CR1R2, CR1OR2, CR1SR2; Y is selected from oxygen, nitrogen, sulfur, NR6, CR6R7; A is C1-C4 alkyl, wherein the alkyl chain may be ted to Y, D, Rb3 and/or Rb5 to form a cycloalkyl or heterocycle; D may be absent or present, and if present is selected from –OR1, –NR1R2; R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 lkyl, sulfonamide, carboxamide, acyl, and nitrile, wherein R1 and R2 may be connected to form a cycloalkyl or a heterocycle; R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, and n; Ra1, Ra2, and Ra3 are independently ed from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, n, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 lkyl; and Rb3 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1- C6 alkoxy, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, and Ra3 is not hydrogen; and if Ra1 and Ra3 are both hydrogen, and Y = nitrogen, then Ra2 is not hydrogen, -OAc, or -OMe. 21. The method according to paragraph 20, wherein U is C=O; Ra2 is selected from hydrogen and amino; Ra1 and Ra3 are independently selected from en and C1-C6 alkoxy; Q is CH; Rb3 is selected from hydrogen, C1-C6 alkyl, and C1-C6 alkoxy; Rb2 and Rb6 are both hydrogen; Y is selected from oxygen; A is C1-C4 alkyl; D may be absent or present, and if present is selected from hydroxy, heterocycle, and NR1R2; and R1 and R2 are independently ed from hydrogen and C1-C6 alkyl. 22. The method ing to paragraph 21, wherein U is C=O; Ra2 is selected from hydrogen and amino; Ra1 and Ra3 are independently selected from hydrogen and C1-C6 alkoxy; Q is CH; Rb3 is selected from hydrogen, methyl, and methoxy; Rb2 and Rb6 are both en; Y is selected from oxygen; A is selected from methyl and ethyl; D may be absent or present, and if present is selected from hydroxy, pyrrolidinyl, and NR1R2; and R1 and R2 are independently selected from hydrogen and acetyl. 23. A method for reducing IL-6 and/or VCAM-1 in a t, comprising administering a therapeutically effective amount of at least one compound selected from: 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-(2-hydroxyethoxy)methylphenyl)-5,7-dimethoxyquinazolin-4(3H)- ,7-dimethoxy(3-methoxy(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 3-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl) methoxyphenoxy)ethyl)acetamide; 2-(3,5-dimethoxyphenyl)(pyridinylamino)quinazolin-4(3H)-one; and ,7-dimethoxy(3-methoxyphenyl)quinazolin-4(3H)-one, or a pharmaceutically acceptable salt or hydrate thereof. 24. The method according to any one of aphs 1 to 23, wherein the therapeutically effective amount of the compound is administered with at least one pharmaceutically acceptable carrier in a ceutically acceptable composition.

. The method according to any one of paragraphs 1 to 24, further sing treating and/or preventing cardiovascular and inflammatory diseases and related disease states, characterized by altered expression of markers of inflammation selected from IL-6 and/or VCAM-1 proliferation. 26. The method according to paragraph 25, wherein the diseases are selected from cardiovascular and inflammatory diseases mediated by IL-6 and/or VCAM-1 proliferation. 27. The method according to any one of paragraphs 1 to 26, n the subject is a human. 28. A compound of Formula I: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q and V are independently selected from CH and en; U is selected from C=O and SO2; W is selected from carbon and nitrogen; Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; Ra1, Ra2, and Ra3 are independently ed from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, n, amino, amide, hydroxyl, heterocycle, and C3-C6 lkyl, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkenyl, C3-C6 cycloalkyl, hydroxyl, and amino; Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 , C3-C6 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle; represents a 3-8 membered ring system wherein: W is selected from carbon and nitrogen; Z is selected from CR6R7, NR8, oxygen, sulfur, , and -SO2-; said ring system being optionally fused to another ring selected from cycloalkyl, cycle, and , and wherein said ring system is optionally selected from rings having the structures R3, R4, and R5 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryl, aryloxy, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 l, C3-C6 cycloalkyl, aryl, halogen, hydroxyl, acyl, and -CN; R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 l, C1-C6 alkynyl, C3- C6 cycloalkyl, and acyl; and R9, R10, R11, and R12 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, aryl, hydroxyl, yl, and acyl, provided that if Q = CH, then at least one of Ra1, Ra2, and Ra3 is not hydrogen; if Z = NAc, then only one of Ra1, Ra2, and Ra3 is hydrogen, and Ra1 is not -OCH2CH2OMe; if Ra1 and Ra3 are both OMe, than R8 is not -C(O)CH2OH; and further provided that the compound of Formula I is not 5,7-dimethoxy(4- morpholinophenyl)quinazolin-4(3H)-one, 5,7-dimethoxy(4-(4-methylpiperazin nyl)quinazolin-4(3H)-one, or 2-(4-(1-cyclopentylpiperidinyl)phenyl) methylquinazolin-4(3H)-one. 29. The nd according to paragraph 28, wherein is R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl , aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, acyl, and C3-C6 cycloalkyl.

. The compound according to paragraph 28, wherein is R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R9 and R10 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 lkyl, aryl, heterocycle, yl, carbamate, amide, and acyl. 31. The compound according to paragraph 28, wherein is N R10 R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 l, C1-C6 alkoxy, C3-C6 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R9 and R10 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, aryl, heterocycle, sulfonyl, carbamate, carboxamide, and acyl. 32. The compound according to paragraph 28, n is R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryloxy, aryl, hydroxyl, amino, amide, oxo, -CN, and sulfonamide; and R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 l, acyl, and C3-C6 cycloalkyl. 33. The compound according to paragraph 28, wherein U is C=O Rc is hydrogen; Ra2 is hydrogen; Ra1 and Ra3 are independently selected from C1-C6 alkoxy, hydrogen, and halogen; Rb2, Rb3, Rb5, and Rb6 are each hydrogen; R3 R3 N R4 R4 is ed from , , , and ; R3 and R4 are ndently selected from hydrogen and C1-C6 alkyl; R8 is selected from C1-C6 alkyl, and hydrogen; and R9, R10, R11, and R12 are independently selected from C1-C6 alkyl, hydrogen, acyl, and sulfonyl. 34. The compound according to paragraph 33, wherein U is C=O Rc is hydrogen; Ra2 is hydrogen; Ra1 and Ra3 are independently selected from methoxy, hydrogen, and halogen; Rb2, Rb3, Rb5, and Rb6 are each hydrogen; R3 R3 N R4 R4 is selected from , , , and ; R3 and R4 are independently selected from en and methyl; R8 is selected from hydrogen, hydroxyethyl, butyl, acetyl, isopropyl, 4- hexanoyl, 4-isobutyryl, benzoyl, 4-fluorobenzoyl, 4-picolinoyl, 4-nicotinoyl, 4- isonicotinoyl, thiophenecarbonyl, 5-chloromethyl-1H-pyrazolecarbonyl, 3,3,3-trifluoropropanoyl, 2,5-dichlorothiopenecarbonyl, cyclopropanecarbonyl, 4-fluorobenzyl, benzyl, 2,2,2-trifluoroethyl, tertbutoxycarbonyl, and formyl; and R9 and R10 are independently selected from hydrogen, methyl, cyclopropylmethyl, and acetyl; and R11 and R12 are ndently selected from hydrogen, , methanesulfonyl, dimethylaminocarbonyl, benzoyl, , ethyl, and isopropyl.

. A nd selected from: 2-(4-((3R,5S)acetyl-3,5-dimethylpiperazinyl)phenyl)-5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2-(4-(4-hydroxypiperidinyl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin- 4(3H)-one; (3R,5S)acetyl-3,5-dimethylpiperazinyl)phenyl)methoxy(2- methoxyethoxy)quinazolin-4(3H)-one; 2-(4-(4-isopropylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-acetylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(piperazinyl)phenyl)quinazolin-4(3H)-one; 4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)acetamide; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)methanesulfonamide 3-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin 1-dimethylurea; 2-(4-(4-hexanoylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-isobutyrylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-benzoylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 4-(4-fluorobenzoyl)piperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)benzamide; ,7-dimethoxy(4-(4-picolinoylpiperazinyl)phenyl)quinazolin-4(3H)-one; ,7-dimethoxy(4-(4-nicotinoylpiperazinyl)phenyl)quinazolin-4(3H)-one; 2-(4-(4-isonicotinoylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)- ,7-dimethoxy(4-(4-(thiophenecarbonyl)piperazin yl)phenyl)quinazolin-4(3H)-one; 2-(4-(4-(5-chloromethyl-1H-pyrazolecarbonyl)piperazinyl)phenyl)- ,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(4-(3,3,3-trifluoropropanoyl)piperazin yl)phenyl)quinazolin-4(3H)-one; 2-(4-(4-(2,5-dichlorothiophenecarbonyl)piperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(4-(cyclopropanecarbonyl)piperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(4-(4-fluorobenzyl)piperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(4-benzylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-(2,2,2-trifluoroethyl)piperazinyl)phenyl)quinazolin-4(3H)-one; 2-(4-(4-butylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(4-acetyl-1,4-diazepanyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)- 2-(4-(1,4-diazepanyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; methoxy(4-(4-methyl-1,4-diazepanyl)phenyl)quinazolin-4(3H)- N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)-N-ethylacetamide; 2-(4-((3R,5S)acetyl-3,5-dimethylpiperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-((3R,5S)-3,5-dimethylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(4-acetylmethylpiperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)pyrrolidin- 3-yl)acetamide; 2-(4-(4-isopropylpiperazinyl)phenyl)methoxyquinazolin-4(3H)-one; 2-(4-(4-(2-hydroxyethyl)piperazinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperidin yl)-N-isopropylacetamide; -chloro(4-(4-isopropylpiperazinyl)phenyl)quinazolin-4(3H)-one; 2-(4-((3R,5S)isopropyl-3,5-dimethylpiperazinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(piperidinyl)phenyl)quinazolin-4(3H)-one; ,7-dimethoxy(4-(3-(methylamino)pyrrolidinyl)phenyl)quinazolin- 4(3H)-one; tert-butyl 4-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolin yl)phenyl)piperidinecarboxylate; 4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)pyrrolidin- 3-yl)-N-methylacetamide; 2-(4-(4-(isopropylamino)piperidinyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(1-acetylpiperidinyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(3-methylpiperazinyl)phenyl)quinazolin-4(3H)-one; N-benzyl-N-(1-(5-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)pyridin- 2-yl)piperidinyl)acetamide; 2-(6-(4-(benzylamino)piperidinyl)pyridinyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 4-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenyl)piperazine carbaldehyde; 2-(4-(2-(1-acetylazetidinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 3-(cyclopropylmethylamino)pyrrolidinyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; and ,7-dimethoxy(4-(4-oxopiperidinyl)phenyl)pyrido[2,3-d]pyrimidin- 4(3H)-one, and pharmaceutically acceptable salts and hydrates thereof. 36. A compound of Formula II: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q and V are ndently selected from CH and nitrogen; U is selected from C=O and S=O; R1 and R2 are independently ed from hydrogen, and C1-C6 alkyl; Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 l, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, amino, amide, hydroxyl, and cycle, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 l, C3-C6 cycloalkyl, hydroxyl, and amino; Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and/or Rb6 may be connected to form a cycloalkyl or a heterocycle; Rn1 is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; and Rn2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, alkenyl, amino, and sulfonyl, wherein Rn1 and/or Rn2 may be connected with Rb3 and/or Rb5 to form a 5- or ered heterocyclic ring, provided that at least one of Ra1, Ra2, and Ra3 is not hydrogen; and Rn1 and Rn2 are not both hydrogen, methyl, ethyl, or -CH2CH2OH. 37. The compound according to paragraph 36, wherein: Q is CH; V is N; U is C=O; Rc is en; Ra2 is hydrogen; Ra1 and Ra3 are each C1-C6 alkyl; Rb2, Rb3, and Rb6 are each hydrogen; Rn1 is hydrogen; Rn2 is selected from sulfonyl, heterocycle, and aryl; and Rb5 is selected from hydrogen or may be connected with Rn2 to form a heterocycle. 38. The compound according to paragraph 37, wherein: Q is CH; V is N; U is C=O; Rc is hydrogen; Ra2 is hydrogen; Ra1 and Ra3 are each methoxy; Rb2, Rb3, and Rb6 are each hydrogen; Rn1 is hydrogen; Rn2 is selected from methanesulfonyl, pyridinyl, ylphenyl, and pyridinyl; and Rb5 is selected from hydrogen or may be connected with Rn2 to form a cycle selected from (2-hydroxymethyl)-1H-pyrrolyl, (2-hydroxyethyl)-1H- pyrrolyl, 2-(pyrrolidinyl-ylmethyl)-1H-pyrrolyl, 3-(hydroxymethyl)-1H- pyrazolyl, 2-(pyrrolidinyl-ylethyl)-1H-pyrrolyl, and 2- ((dimethylamino)methyl)-1H-pyrrolyl. 39. A compound selected from: 2-(2-(hydroxymethyl)-1H-indolyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-(2-hydroxyethyl)-1H-indolyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(2-(pyrrolidinylmethyl)-1H-indolyl)quinazolin-4(3H)- hydroxymethyl)-1H-indazolyl)-5,7-dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(2-(2-(pyrrolidinyl)ethyl)-1H-indolyl)quinazolin-4(3H)- 2-(2-((dimethylamino)methyl)-1H-indolyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolin yl)phenyl)methanesulfonamide; ,7-dimethoxy(4-(pyridinylamino)phenyl)quinazolin-4(3H)-one; methoxy(4-(p-tolylamino)phenyl)quinazolin-4(3H)-one; and ,7-dimethoxy(4-(pyridinylamino)phenyl)quinazolin-4(3H)-one, and pharmaceutically acceptable salts and hydrates thereof. 40. A compound of Formula III: (III) or a isomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q is selected from CR12 and nitrogen; V is selected from CH and nitrogen; U is selected from C=O, S=O, and SO2; X is selected from oxygen, nitrogen, , NR6R7, and CR6R7; Z is selected from unsubstituted C1-C6 alkyl and C1-C6 alkyl substituted with one or more groups selected from C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, hydroxyl, amino, and halogen; n is selected from 0, 1, 2, 3, 4, or 5; G is selected from heterocycle, cycloalkyl, and aryl; R6, R7, and R12 are independently selected from hydrogen, C1-C6 alkyl, C3- C6 cycloalkyl, C1-C6 alkoxy, and n; Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 lkyl; Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, n, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 lkyl, C1-C6 alkenyl, hydroxyl, and amino; and Rb3 and Rb5 are ndently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle; provided that if X = oxygen and n is 3, then Rc is hydrogen; at least one of Ra1, Ra2, and Ra3 is not hydrogen; if Ra2 or Ra3 is chloro, then Ra1 is not hydrogen if Ra1 and Ra3 are OMe, and Q = CH, then is not H O O N N O N O N N Ph NAc O , O , or ; if Ra1 and Ra3 are OMe and Ra2 is en, then is not O ; and further provided that the compound of Formula III is not 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one, 2-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione, 3-(3,5-dimethyl(2-(4- methylpiperazinyl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one, (4- ethylpiperazinyl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one, ,7-dimethoxy(4-((4-methylpiperazinyl)methyl)phenyl)quinazolin-4(3H)-one, ,7-dimethoxy(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one. 41. The compound according to paragraph 40, wherein: Q is ed from CR12 and nitrogen; V is selected from nitrogen; R12 is selected from C1-C6 alkoxy, and halogen; Rc is selected from hydrogen and C1-C6 alkyl; Ra2 is selected from hydrogen and C1-C6 alkoxy; Ra1 and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, n, and heterocycle; Rb2 and Rb6 are both hydrogen; Rb3 and Rb5 are independently selected from hydrogen and C1-C6 alkyl; X is selected from oxygen and CH2; n is ed from 0, 1, 2, 3, or 4; and G is selected from heterocycle, cycloalkyl, and aryl. 42. The compound according to aph 41, wherein: Q is selected from CR12 and nitrogen; V is selected from nitrogen; R12 is selected from methoxy and chlorine; Rc is selected from hydrogen and (pyrrolidinyl)propyl; Ra2 is selected from hydrogen and methoxy; Ra1 and Ra3 are independently selected from hydrogen, methyl, chlorine, ne, methoxy, poxy, and pyrrolidinyl; Rb2 and Rb6 are both hydrogen; Rb3 and Rb5 are independently selected from hydrogen and methyl; and is selected from (N,N-dimethylpiperidinecarboxamide)oxy, 1- acetylpiperidinyloxy, 2-(isoindolinyl)ethoxy, 2-(pyrrolidinyl)ethoxy, 3- (pyrrolidinyl)propoxy, 4-(pyrrolidinyl)butoxy, (4-acetylpiperazinyl)ethoxy, (1H-imidazolyl)ethoxy, hylpiperazinyl)ethoxy, idinyl)ethoxy, (1-isopropylimidazolidine-2,4-dione)ethoxy, (5-phenylimidazolidine-2,4-dione)- 3-ethoxy, (imidazolidine-2,4-dione)methyl, (2-azepanyl)ethoxy, (2-azetidin yl)ethoxy, N-(azetidinyl)acetamideethoxy, (isoindoline-1,3-dione)ethoxy, (5-oxopyrrolidinyl)methoxy, (4-isopropylpiperazinyl)methyl, N-isopropyl-N- (piperidinmethyl)acetamidemethyl, (4-(isopropylamino)piperidinyl)methyl, (pyrrolidine-2,5-dione)ethoxy, and (1H-tetrazolyl)methyl. 43. A compound selected from: 4-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)phenoxy)-N,N- dimethylpiperidinecarboxamide; 1-acetylpiperidinyloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-(isoindolinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 4(3H)-one; ,7-dichloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 2-(3,5-dimethyl(3-(pyrrolidinyl)propoxy)phenyl)-5,7-dimethoxy(3- (pyrrolidinyl)propyl)quinazolin-4(3H)-one; 2-(4-(2-(4-acetylpiperazinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(1H-imidazolyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 2-(3,5-dimethyl(2-(4-methylpiperazinyl)ethoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(piperidinyl)ethoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(3-methyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 3-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)isopropylimidazolidine-2,4-dione; 2-(3,5-dimethyl(3-(pyrrolidinyl)propoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; ,7-dimethoxy(4-(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)-one; 2-(3,5-dimethyl(3-(pyrrolidinyl)propyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(4-(pyrrolidinyl)butoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 4(3H)-one; 3-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)phenylimidazolidine-2,4-dione; 3-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)benzyl)imidazolidine- 2,4-dione; -dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)fluoro(pyrrolidin yl)quinazolin-4(3H)-one; -chloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 2-(4-(2-(azepanyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-difluoroquinazolin- 4(3H)-one; 2-(4-(2-(azetidinyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)azetidinyl)acetamide; -dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- diisopropoxyquinazolin-4(3H)-one; 8-chloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-dimethylquinazolin- 4(3H)-one; 2-(2-(4-(6,8-dimethoxyoxo-1,2-dihydroisoquinolinyl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7- diisopropoxypyrido[2,3-d]pyrimidin-4(3H)-one; (S)(3,5-dimethyl((5-oxopyrrolidinyl)methoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-((4-isopropylpiperazinyl)methyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; N-(1-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)benzyl)piperidin yl)-N-isopropylacetamide; 2-(4-((4-(isopropylamino)piperidinyl)methyl)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-((1H-tetrazolyl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 1-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)pyrrolidine-2,5-dione, and pharmaceutically acceptable salts and hydrates thereof. 44. A compound of Formula IV: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q1 is selected from nitrogen and C-Ra1; Q2 is selected from nitrogen and C-Ra2; Q3 is selected from nitrogen and C-Ra3; V is selected from CH and nitrogen; U is selected from C=O and S=O; Ra1, Ra2, and Ra3 are independently ed from en, C1-C6 alkyl, C1-C6 l, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and heterocycle, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 lkyl, C1-C6 alkenyl, hydroxyl, and amino; and Rb3 and Rb5 are independently selected from en, methyl, ethyl, C3- C6 cycloalkyl, C1-C3 alkoxy, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, and Ra3 is hydrogen; if Ra3 is alkoxy, then Ra1 is not hydrogen; N N if Ra2 is or O , then Rb 3 is not hydrogen; if Rb2, Rb5, and Rb6 are hydrogen, then Rb3 is not -CH2OH; and one of Rb3 and Rb5 is not hydrogen. 45. The compound according to paragraph 44, wherein: U is C=O; V is nitrogen; Rb2 and Rb6 are both en; Rb3 and Rb5 are independently selected from C1-C6 alkyl and hydrogen; Q2 is selected from C1-C6 alkyl and hydrogen; and Q1 and Q3 are independently selected from hydrogen and C1-C6 alkoxy. 46. The nd according to paragraph 45, wherein: U is C=O; V is nitrogen; Rb2 and Rb6 are both hydrogen; Rb3 and Rb5 are independently ed from methyl and hydrogen; Q2 is selected from hydrogen, hylpiperazinyl)methyl, morpholinoethyl, morpholinomethyl, and (pyrrolidinyl)ethyl; and Q1 and Q3 are independently selected from hydrogen, benzyloxyethoxy, methoxy, methoxyethoxy, (pyrrolidinyl)ethoxy, phenoxyethoxy, and isopropoxyethoxy. 47. A compound selected from: 7-(2-(benzyloxy)ethoxy)methoxy(pyridinyl)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)-5,7-dimethoxyquinazolin-4(3H)-one; -dimethylpyridinyl)methoxy(2-methoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-(pyrrolidin yl)ethoxy)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)((4-methylpiperazinyl)methyl)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-phenoxyethoxy)quinazolin- 2-(2,6-dimethylpyridinyl)methoxy(2-phenoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-methoxyethoxy)quinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)methoxy(2-(pyrrolidin yl)ethoxy)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)(2-isopropoxyethoxy)methoxyquinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)-5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)- 7-(2-(benzyloxy)ethoxy)(2,6-dimethylpyridinyl)methoxyquinazolin- 4(3H)-one; 2-(2,6-dimethylpyridinyl)(2-morpholinoethyl)quinazolin-4(3H)-one; 2-(2-methylpyridinyl)(morpholinomethyl)quinazolin-4(3H)-one; -methoxy(2-methoxyethoxy)(2-methylpyridinyl)quinazolin-4(3H)- 2-(2,6-dimethylpyridinyl)(2-(pyrrolidinyl)ethyl)quinazolin-4(3H)-one; 2-(2,6-dimethylpyridinyl)(2-isopropoxyethoxy)methoxyquinazolin- 4(3H)-one; and 2-(2,6-dimethylpyridinyl)(2-methoxyethoxy)(2-(pyrrolidin yl)ethoxy)quinazolin-4(3H)-one, and pharmaceutically acceptable salts and hydrates f. 48. A compound of the Formula V: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: Q is selected from CR6 and nitrogen; U is selected from C=O and SO2; Y is selected from oxygen, en, sulfur, NR6, CR6R7; A is C1-C4 alkyl, wherein the alkyl chain may be connected to Y, D, Rb3 and/or Rb5 to form a cycloalkyl or heterocycle; D may be absent or present, and if present is selected from –OR1, –NR1R2; R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, sulfonamide, carboxamide, acyl, and nitrile, wherein R1 and R2 may be connected to form a cycloalkyl or a heterocycle; R6 and R7 are ndently ed from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 , yl, and halogen; Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, n, amino, amide, hydroxyl, and heterocycle, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle; Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl; and Rb3 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1- C6 alkoxy, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, and Ra3 is not hydrogen; if Ra1 and Ra3 are both hydrogen, and Y = nitrogen, then Ra2 is not hydrogen, -OAc, or -OMe; and further provided that the compound of Formula V is 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one. 49. The compound ing to paragraph 48, wherein: U is C=O; Ra2 is selected from hydrogen and amino; Ra1 and Ra3 are independently selected from hydrogen and C1-C6 alkoxy; Q is CH; Rb3 is ed from hydrogen, C1-C6 alkyl, and C1-C6 alkoxy; Rb2 and Rb6 are both en; Y is selected from oxygen; A is C1-C4 alkyl; D may be absent or present, and if present is selected from hydroxy, heterocycle, and NR1R2; and R1 and R2 are independently selected from hydrogen and C1-C6 alkyl. 50. The nd according to paragraph 49, wherein: U is C=O; Ra2 is selected from hydrogen and amino; Ra1 and Ra3 are independently selected from hydrogen and C1-C6 alkoxy; Q is CH; Rb3 is selected from hydrogen, methyl, and methoxy; Rb2 and Rb6 are both hydrogen; Y is selected from oxygen; A is selected from methyl and ethyl; D may be absent or present, and if present is selected from hydroxy, pyrrolidinyl, and NR1R2; and R1 and R2 are independently selected from en and acetyl. 51. A nd selected from: 2-(3-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-(2-hydroxyethoxy)methylphenyl)-5,7-dimethoxyquinazolin-4(3H)- ,7-dimethoxy(3-methoxy(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin- 4(3H)-one; N-(2-(3-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl) methoxyphenoxy)ethyl)acetamide; 2-(3,5-dimethoxyphenyl)(pyridinylamino)quinazolin-4(3H)-one; and ,7-dimethoxy(3-methoxyphenyl)quinazolin-4(3H)-one, and pharmaceutically acceptable salts and hydrates thereof. 52. A pharmaceutical composition sing a compound of any one of paragraphs 28 to 51 and a pharmaceutically acceptable carrier. 53. A method for reducing IL-6 and/or VCAM-1 in a subject, comprising administering a therapeutically effective amount of at least one nd according to paragraphs 28 to 51 or a composition according to paragraph 52. 54. The method according to paragraph 53, further comprising treating and/or preventing cardiovascular and matory diseases and d disease , characterized by altered expression of markers of inflammation selected from IL-6 and/or VCAM-1 proliferation. 55. The method according to paragraph 45, wherein the diseases are selected from cardiovascular and inflammatory diseases mediated by IL-6 and/or VCAM-1. 56. The method according to any one of aphs 53 to 55, wherein the subject is a human. 57. The use of a compound according to any one of paragraphs 28 to 51 in the manufacture of a medicament for the treatment or tion of cardiovascular and inflammatory diseases mediated by IL-6 and/or VCAM-1.

Still further embodiments are within the scope of the following claims.

I/WE

Claims (2)

CLAIM :

1. A compound selected from: 2-(4-(2-(isoindolinyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin-4(3H)- chloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)- 2-(3,5-dimethyl(3-(pyrrolidinyl)propoxy)phenyl)-5,7-dimethoxy(3- (pyrrolidinyl)propyl)quinazolin-4(3H)-one; 2-(4-acetylpiperazinyl)ethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(4-(2-(1H-imidazolyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin-4(3H)- 2-(3,5-dimethyl(2-(4-methylpiperazinyl)ethoxy)phenyl)-5,7- dimethoxyquinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(piperidinyl)ethoxy)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 5,7-dimethoxy(3-methyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)- 3-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- ylphenoxy)ethyl)isopropylimidazolidine-2,4-dione; 2-(3,5-dimethyl(3-(pyrrolidinyl)propoxy)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 5,7-dimethoxy(4-(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)-one; 2-(3,5-dimethyl(3-(pyrrolidinyl)propyl)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(4-(pyrrolidinyl)butoxy)phenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin-4(3H)- 4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)phenylimidazolidine-2,4-dione; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)methoxyquinazolin-4(3H)- 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-dimethoxypyrido[2,3- d]pyrimidin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)fluoro(pyrrolidin nazolin-4(3H)-one; 5-chloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)-one; 2-(4-(2-(azepanyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)- 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-difluoroquinazolin-4(3H)- 2-(4-(2-(azetidinyl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- 4(3H)-one; 2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)azetidinyl)acetamide; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-diisopropoxyquinazolin- 4(3H)-one; 8-chloro(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-4(3H)-one; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-dimethylquinazolin-4(3H)- 2-(2-(4-(6,8-dimethoxyoxo-1,2-dihydroisoquinolinyl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione; 2-(3,5-dimethyl(2-(pyrrolidinyl)ethoxy)phenyl)-5,7-diisopropoxypyrido[2,3- d]pyrimidin-4(3H)-one; 2-(4-((4-isopropylpiperazinyl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)- one; and 1-(2-(4-(5,7-dimethoxyoxo-3,4-dihydroquinazolinyl)-2,6- dimethylphenoxy)ethyl)pyrrolidine-2,5-dione, or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof.

2. A pharmaceutical composition comprising a compound of claim 1 or a tautomer, stereoisomer, pharmaceutically able salt or hydrate thereof, and a ceutically acceptable carrier. Resverlogix Corp. By the Attorneys for the Applicant SPRUSON & FERGUSON